Months Of Hematopoietic Stem Cell Transplantation Research Articles

Acute Pulmonary Toxicity after Allogeneic Stem Cell Transplantation Using Total Body Irradiation-Based Conditioning- Myeloablative vs. Non-Myeloablative Regimens

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with a high risk of acute pulmonary toxicity, especially with total body irradiation-based (TBI) conditioning regimens. High-grade acute pulmonary toxicity occurs in ∼30% of patients when a myeloablative regimen is utilized (∼12-14 Gy). The risk of pulmonary toxicity with non-myeloablative regimens (∼2 Gy) is not well described. We evaluated the incidence and predictors of acute pulmonary toxicity after HSCT comparing myeloablative and non-myeloablative TBI-based conditioning regimens. All adult (≥ 18 y/o) patients undergoing allogeneic HSCT with TBI (1995-2020) at our institution were evaluated. The dose to the lungs was attenuated to 7-10 Gy in all patients undergoing myeloablative TBI. Acute pulmonary toxicity, occurring within 6 months of HSCT, was scored using CTCAE v5.0. The incidence of acute pulmonary toxicity was calculated using the Kaplan-Meier method, and logistic regression was performed to assess for independent risk factors. Five hundred fifty-two patients were included the analysis (myeloablative- 378; non-myeloablative- 174). Myeloablative TBI was most commonly 13.5 Gy/9Fx (335/378), while non-myeloablative TBI was delivered most often as 2 Gy/1Fx (165/174). Patients undergoing myeloablative TBI were younger than non-myeloablative patients (43 vs 58 years, p<0.001), but baseline pulmonary function parameters were similar. At 6 months after transplant, the cumulative incidences of any acute pulmonary toxicity for patients receiving myeloablative and non-myeloablative TBI were 39% and 33%, respectively (p = 0.11). The risk of low-grade (1-2) and high grade (3-5) pulmonary toxicity was 10% vs 12% (p = 0.59) and 28% vs 21% (p = 0.05), respectively, comparing myeloablative and non-myeloablative TBI. Proportions of high-grade toxicities among the myeloablative and non-myeloablative cohorts were as follows: infectious pneumonia (31% and 49%), bronchopulmonary hemorrhage (25% and 3%), respiratory failure NOS (17% and 10%), pleural effusion (5% and 1%), and pneumonitis (4% and 0%). Female sex (OR 1.52, p = 0.05) and refractory disease at the time of transplant (OR 2.25, p = 0.03) were associated with a higher risk of severe pulmonary toxicity on logistic regression. Younger age (OR 0.99, p = 0.35) and non-myeloablative TBI (OR 0.21, p = 0.60) were not significantly associated with a lower risk. The risk of acute pulmonary toxicity was high with both myeloablative and non-myeloablative TBI-based regimens, though high-grade toxicity was modestly higher in the myeloablative cohort. A better understanding of pulmonary toxicity in the setting of non-myeloablative TBI (∼2 Gy) is needed.

CD19-CAR-T Cells Are Effective and Safe Treatment of Post-Transplant Relapse in Pediatric and Young Adult Patients with B-Lineage ALL: Real-World Data from Germany

Introduction: Patients with precursor-B acute lymphoblastic leukemia (pre-B ALL) which have relapsed subsequent to allogeneic hematopoietic stem cell transplantation (HSCT), have relapsed twice, or were resistant to upfront therapy have a dismal prognosis. CD19-directed chimeric antigen receptor (CAR) T cells have evolved as potent immune therapy for such patients. Tisagenlecleucel (Tisa-cel) is a commercial CD19-directed autologous CAR-T cell product. The CAR contains the co-stimulatory element 4-1BB to promote in vivo persistence and proliferation. Thus this therapy is in principle competent to serve as a stand-alone therapy. Based on the results of the ELIANA trial (Maude et al. NEJM 2017), Tisa-cel was approved by FDA and EMA for pediatric/young adult B-ALL in 2017 and 2018. In clinical trials, stringent inclusion criteria narrow down the risk profiles of trial subjects. Treatment in clinical trials provides close guidance to physicians and patients during the trial. However, post approval reality leads to treatment of patients with higher and more variable risk profiles treated in many centers. With approval by the local ethics committees, we performed a retrospective study asking all CAR T cell centers in Germany approved for treatment with Tisa-cel (Kymriah®) to provide treatment data reflecting post approval reality, in order to identify patients who might most benefit from this novel, complex and expensive treatment. Patients: Twenty-one centers included all pediatric and young adult patients with pre-B ALL (n=81) who had received Tisa-cel between 8/2018-1/2022, allowing for a minimal follow-up of 5 months of surviving patients. Median age was 11.5 years (range: 1.0-25.0 years), 53 (65.4%) were male and 28 (34.6%) female, median body weight was 41.6 kg (range: 8.0 kg-135 kg). 65 patients (80.2%) had relapsed after HSCT, 15 (18.5%) had suffered a 2nd relapse without HSCT and 1 had primary refractory disease. For bridging therapy, 3 patients (3.7%) received Blinatumomab, 4 (4.9%) inotuzumab, 72 (88.9%) received low-dose chemotherapy. One patient was bridged with a high-dose chemotherapy; 1 patient with extra-medullary disease did not receive any bridging therapy. Results: Cytokine release syndrome (CRS) was observed in 55 (67.9%) patients (grade I-II: n=50, Grade III-IV: n=4 and grade V: n=1); immune cell-associated neurological syndrome (ICANS) was seen in 6 (7.4%) patients (grade I: n=2, grade III-IV: n=4). At day 28, 72 patients (88.9%) were in CR, 8 (9.9%) in NR. One patient (1.2%) succumbed to CRS. At last follow-up, 42 patients (60%) remained in remission, 34 patients had relapsed, 1 died of TRM, 3 of NRM, 1 had developed secondary MDS. This translated into an event-free survival probability (pEFS) of 43.9% (±6.5), an of overall survival (pOS) of 52.9% (±7.0), and a cumulative incidence of relapse (CIR) of 48.8% (±6.4) at 2 years post CAR T cell transfusion. CIR CD19 neg. was 33.8% (±6.1%) and CIR CD19 pos. was 15% (±4.2%). Interestingly, there was no difference between children and adult patients with regard to pEFS and pOS. A trend towards a higher pEFS (n=16, 55.0±12.7%) compared to patients receiving CAR-T for relapse after alloHSCT (n=65, 41.8±7.2%) was observed (p=0.630). Time to relapse after HSCT was a strong predictor for outcome. Patients relapsing within 6 months of HSCT had a pEFS (pOS) of 17.2±9.6% (15.6±9.6%), pEFS (pOS) for those relapsing later was 53.8±9.0% (74.5±8.0%) p=0.001), Figure 1. Risk factors: For the subgroup with post HSCT relapse, multivariable Cox-regression analysis considering age, time from HSCT to relapse, extra-medullary relapse, remission status at start of lymphodepleting chemotherapy (LDC) and LDC dosing revealed that time from HSCT to relapse >6 months’ post HSCT as a single factor reduced the risk to 0.381 and 0.221, respectively (p=0.001 and p=0.003), Table 1. Conclusion: In our analysis providing the first real-world experience in a patient cohort highly enriched for patients with post HSCT relapse, 40% of ALL patients with poor prognosis were rescued with a single dose of Tisa-cel. Our novel finding that patients post HSCT had a far better EFS if relapse occurred beyond 6 months might be attributable to more competent T-cell system with more native T-cells with higher plasticity for proliferation, expansion and persistence. This is currently a matter of investigation and may in future allow to implement strategies to optimize CAR T cell therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation

Hepatitis B virus (HBV) reactivation reportedly occurs frequently after hematopoietic stem cell transplantation (HSCT) in resolved HBV-infected patients. Here, 50 patients with resolved HBV infections and scheduled to undergo HSCT were enrolled; all subjects were vaccinated with three doses of hepatitis B vaccine 12 months after HSCT and the incidence of HBV reactivation was monitored. The patients’ characteristics were: median age, 61 (34–72) years; male/female, 27/19; allogeneic/autologous, 40/6; bone marrow/peripheral blood stem cells/cord blood, 26/16/4. Of the 46 patients who underwent HSCT, 19 were excluded and did not make it to vaccination due to relapse of underlying disease, HBV reactivation within 12 months of HSCT, or transfer of patients. The remaining 27 were vaccinated 12 months after HSCT and monitored for 2 years. Six showed HBV reactivation, with a 2-year cumulative reactivation incidence of 22.2%; the same incidence was 27.3% only in allogeneic HSCT patients. Factors associated with HBV reactivation included the discontinuation of immunosuppressants (P = 0.0379) and baseline titers of antibody against hepatitis B surface antigen (P = 0.004). HBV reactivation with vaccination following HSCT could occur despite maintenance of serum anti-HBs at more than protective levels.

The Economic and Health Utilization Cost of Clinically Significant Cytomegalovirus Infection Following Allogeneic Hematopoietic Cell Transplantation

Introduction Understanding the economic impact of managing allogeneic hematopoietic stem cell transplant (HCT) recipients with cytomegalovirus (CMV) is important for future planning within institutional transplant programs. CMV remains the most frequent viral infection following HCT but less is known about the impact of CMV on health resource utilization. Objectives We aimed to evaluate the economic burden of CMV infection in a large HCT centre operating under a universal health care system. Methods A retrospective single centre study at the Royal Melbourne Hospital, Australia was performed on all allogeneic HCT recipients between Jan2015 to Dec2017. CMV pre-emptive monitoring using quantitative CMV viral load was performed from time of transplant to 100 days or longer if GVHD. Clinically significant CMV (csCMV) was defined as viremia requiring anti-CMV treatment. First line anti-CMV therapy was (val)ganciclovir and second-line therapy was foscarnet. Hospital costing data for all admissions in the first 12 months were obtained. Financial year costing was available for FY2015/2016 to FY2017/2018. Ethics was approved by the Melbourne Health Human Ethics Review Committee (HREC 2017.368). Results A total of 255 patients underwent alloHCT with a median age of 51 years (IQR 40-59). The most common underlying diagnosis was AML (41%) and 54% had unrelated donor transplants. Pre-transplant recipient CMV seropositivity was 62% (n=158), of whom 139 had detectable CMV viremia and 105 (41.2%) experienced clinically significant CMV (csCMV). The median duration of CMV treatment was 33 days (IQR 21-63). Re-admission to hospital within the first 12 months of HCT occurred in 78.4%. There was a greater number of admissions observed in csCMV patients compared to no csCMV (median 3 vs 2, p=0.001) with the duration of admitted days within the first 12 months being significantly greater in csCMV patients compared to no csCMV (median 65 vs 36 days, p Conclusion The health care cost and resource utilization of treating CMV infection following an allogeneic HSCT is substantial and places a heavy burden on limited health resources. In this study, patients experiencing csCMV had an increased number and longer total duration of admissions days compared to patients who did not require CMV treatment. Interventions aimed at reducing the burden of CMV in alloHCT recipients are required.

Letermovir for Primary Cytomegalovirus Prevention in Haploidentical Stem Cell Transplant Recipients

<h3>Introduction</h3> Cytomegalovirus (CMV) continues to be a leading cause of morbidity and mortality among recipients of allogeneic hematopoietic stem cell transplant (HSCT). Marty et al. demonstrated the utility of letermovir for primary prophylaxis. However, a majority of the population in their study (69.4%) received a matched-unrelated or a matched-sibling donor transplant. Therefore, data is limited on optimal CMV prophylaxis among haploidentical recipients. <h3>Objectives</h3> The primary objective of this study was incidence of CMV reactivation prior to and beyond day 100 among haploidentical HSCT recipients who received primary letermovir prophylaxis. Secondary endpoints included median time to reactivation, median time to engraftment, and non-relapse mortality. <h3>Methods</h3> We conducted a single-center retrospective analysis to evaluate the efficacy of letermovir as primary prophylaxis among CMV seropositive haploidentical recipients between May 2018 to December 2019. Patients received letermovir prophylaxis from day 16 to 100. Exclusion criteria included subjects with history of CMV end-organ disease within 6 months of HSCT, history of CMV viremia at any time prior to transplant, received either ganciclovir, valganciclovir, foscarnet, or cidofovir within 7 days of transplant. <h3>Results</h3> We identified 20 haploidentical HSCT recipients, median age 52 years, the majority of which received reduced-intensity conditioning therapy with fludarabine, cyclophosphamide, and total-body irradiation. Graft-versus-host disease prophylaxis included tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. CMV reactivation occurred in 5 patients before day 100 (25%) range (day 20 to 45). Of the remaining 15 patients, an additional 4 (27%) had CMV reactivation after letermovir was discontinued at day 100, range (day 117 to 156). Overall survival at 1 year was 79.2% and non-relapse mortality at 1 year was 12.5%. <h3>Conclusion</h3> Our study demonstrated the efficacy of letermovir as primary prophylaxis among CMV seropositive haploidentical recipients. However, significant CMV reactivation was seen beyond day 100 and future studies need to be conducted on the ideal duration of prophylaxis in this high-risk population.

The Economic and Health Utilization Cost of Clinically Significant Cytomegalovirus Infection Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Understanding the economic impact of managing allogeneic hematopoietic stem cell transplant (HSCT) recipients with cytomegalovirus (CMV) is important for future planning within institutional transplant programs. CMV remains the most frequent viral infection following HSCT of which the clinical impact on transplant outcomes has been well described. However, much less is known about the impact of CMV on health resource utilisation, re-admissions and hospital costs. In addition to antiviral therapy, there are nursing, medical and pharmacy costs to consider. We therefore undertook a study to evaluate the clinical and economic burden of CMV infection following HSCT in a large Australian transplant centre operating under a universal health care system. Methods A retrospective single centre study at the Royal Melbourne Hospital, Melbourne, Australia was performed on all consecutive allogeneic HSCT recipients between January 2015 to December 2017. CMV pre-emptive monitoring using quantitative CMV plasma viral load was performed twice weekly from time of transplant to 100 days or longer in the presence of graft versus host disease. Clinically significant CMV (csCMV) was defined as patients receiving anti-CMV treatment, often with a plasma CMV viral load &amp;gt;400 IU/ml. Throughout the study period, the first line anti-CMV therapy was ganciclovir; either as oral valganciclovir for outpatient management in asymptomatic patients or IV ganciclovir as an inpatient for patients with concerns about oral absorption. Second-line therapy was IV foscarnet. Hospital costing data for the first and subsequent re-admissions for the first 12 months were obtained from the business intelligence unit. Financial year costing was available for FY2015/2016 to FY2017/2018. Ethics was approved by the Melbourne Health Human Ethics Review Committee (HREC 2017.368). Results A total of 255 patients underwent alloHSCT with a median age of 51 years (IQR 40-59) with the most common underlying diagnoses being AML (41%), ALL (11%) and MDS (11%) (Table 1). Thirty-one percent of transplants used myeloablative conditioning, 54% had unrelated donors and 3% had an umbilical cord source. Pre-transplant recipient CMV seropositivity was 62% (n=158), of whom 139 had detectable CMV viremia and 104 (40.8%) experienced clinically significant CMV (csCMV). The median duration of CMV treatment was 33 days (IQR 21-63). Re-admission to hospital within the first 12 months of HSCT occurred in 78.4%. There was a greater number of admissions observed in csCMV patients compared to no csCMV (median 3 vs 2 admissions, p=0.001) with the duration of admitted days within the first 12 months being significantly greater in csCMV patients compared to no csCMV (median 65 vs 36 days, p&amp;lt;0.00001). The mean total cost of treating patients with csCMV for the first 12 months compared to the total cost for patients not requiring CMV treatment was A$196,822 (US$147,616) and A$114503 (US $85,877) (p&amp;lt;0.0001), respectively. Therefore the crude attributable mean cost of treating csCMV was A$82,319 (US$61,739) per patient for the first 12 months of HSCT. The greatest significant contributory costs were from pharmacy A$17,807 (US$13,355), nursing A$16,944 (US$12,708) and medical A$5,898 (US$4,423). Conclusions The health care cost and resource utilisation of treating CMV infection following an allogeneic HSCT is substantial and places a heavy burden on limited health resources. In this study, patients experiencing csCMV had an increased number and longer total duration of admissions days compared to patients who did not require CMV treatment. Interventions aimed at reducing the burden of CMV in alloHSCT recipients are required. Disclosures Yong: Merck Ltd: Honoraria. Bajel:AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: travel funding. Ritchie:Sanofi: Honoraria; Novartis: Honoraria; Imago: Research Funding; Beigene: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Research Funding. Slavin:Merck Ltd: Honoraria, Research Funding.

Risk Factors and Predictive Scoring System for Post-Transplant Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation

Risk Factors and Predictive Scoring System for Post-Transplant Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation

The impact of posttraumatic stress symptoms on social support and social conflict during hematopoietic stem cell transplant

ABSTRACTPurpose/Objectives: Social support and its relationship to psychological distress are of interest in hematopoietic stem cell transplant (HSCT) as patients are dependent on caregivers pre-, during, and posttransplant. Although social support is critical for managing stress and trauma, posttraumatic stress symptoms (PTSS) may erode social support and evoke conflict and abandonment within the support system. This study aimed to evaluate whether PTSS were associated with lower support and social conflict in a sample of patients undergoing HSCT. Design/Methods: Prospective relationships between PTSS, perceived social support, and social conflict were assessed in 88 participants across the first three months of HSCT (T0 Baseline; T1 +30; T2 +60; T3 +90). Findings: When individuals experienced increase above their own average levels of PTSS, they reported concurrent increase in social conflict (p < .001) and subsequent increase in social support in the following month (p = .026). Conclusion/Implications: Results suggest PTSS during stem cell transplantation may evoke social conflict, but over time, the support system may recalibrate to be more supportive. Patients undergoing HSCT may benefit from family and social-level interventions that specifically target the incidence of interpersonal conflict as it unfolds during the initial stages of HSCT.

Cytomegalovirus Management in Adult Hematopoietic Stem Cell Transplant Patients with Pre-Engraftment Viremia: A Single-Center, Retrospective, Descriptive Study

BackgroundScant data exist regarding cytomegalovirus (CMV) viremia in hematopoietic stem cell transplant (HSCT) recipients during the pre-engraftment period. The goal of this study was to describe management of CMV in neutropenic adult HSCT patients at our institution, and to assess the possible impact of different quantitative CMV PCR tests (QPCRs).MethodsPost-HSCT monitoring at this center includes weekly CMV QPCR from plasma. Three different QPCR assays were used sequentially during the study period (1/2010–12/2015): two with lower limits of quantification (LLOQ) of 300 and 100 copies/mL through 4/2013, and after that the FDA-approved assay with LLOQ of 137 IU/mL. Medical records of first-time HSCT patients were reviewed. Pre-/peri-engraftment CMV was defined as detectable CMV DNA with [ANC] < 1000 cells/mm3. Information collected included demographics, donor/recipient CMV serostatus, conditioning regimen, CMV QPCR and ANC results, dates of CMV treatment, CMV disease within 100 days, and death within 6 months of HSCT. Data were analyzed with STATA v14.ResultsOf 1151 total HSCT, 76 patients had a positive CMV QPCR when ANC < 1000 cells/mm3. CMV was first detected a median of 12 days (0–48) post-transplant, and was above LLOQ at a median of 28 days (0–49). 71/76 (93%) were treated at a median of 33 days post-transplant (range 4–105 days), most with valganciclovir (40) or ganciclovir (30); 1 received foscarnet initially. 5 patients with low-level viremia were monitored without treatment. At initiation of therapy, median CMV level was 1471 (range 159–22,900) copies or IU/mL and ANC was 1202 (range 28–9680) cells/mm3. Median treatment duration was 34 days (range 9–392). Only 2 patients had possible tissue-invasive CMV disease.ConclusionGanciclovir and valganciclovir were used to treat most pre- and peri-engraftment CMV viremia, despite potential bone marrow toxicity. The LLOQ of different CMV QPCR tests did not affect the viral threshold for starting treatment. The time between first CMV DNA detection (median day +12) and initiation of treatment (median day +33) suggests clinicians waited for CMV DNA and/or ANC to rise before treating. With this deferred-treatment approach, the proportion of patients with tissue-invasive disease remained low.Disclosures All authors: No reported disclosures.

Retrospective Study Evaluating Hematological Remission Rates and Survival in Chinese Adults with Relapsed or Refractory (r/r) Philadelphia Chromosome Negative (Ph-) B-Precursor Acute Lymphoblastic Leukemia (ALL)

Introduction: Outcomes are poor among Chinese adults with r/r ALL. Current recommendations in China for the treatment of adults with Ph- ALL include induction therapy with vincristine or vindesine, anthracyclines/anthraquinones, and corticosteroids; intensive consolidation therapy following complete remission (CR); and hematopoietic stem cell transplantation (HSCT). Currently, there is a lack of studies assessing treatment status and outcomes in Chinese adults with r/r ALL. The objective of this study was to assess the efficacy of currently available treatments for adults with r/r Ph- ALL in China.Methods: Between January 2009 and December 2014, adults with r/r B-precursor ALL and defined Philadelphia chromosome status were identified and enrolled from 14 hematology centers in China. All patients were ≥ 15 years of age at time of de novo (initial) diagnosis of ALL, had no central nervous system involvement at time of relapse, and had no isolated extramedullary relapse. Clinical data were retrospectively collected by chart review. The primary analysis set included only patients with r/r Ph- ALL, defined as meeting 1 of the following criteria: primary refractory, had relapsed within 12 months of first CR, relapsed after first or later salvage, or relapsed within 12 months of HSCT. The primary endpoint was rate of overall response (CR or CR with partial hematologic recovery [CRh]) after last salvage treatment. Key secondary endpoints included rate of CR with incomplete hematologic recovery (CR/CRh/CRi), duration of CR/CRh, rate of allogeneic hematopoietic stem cell transplantation (alloHSCT) realization after CR/CRh, and overall survival (OS).Results: Of 458 eligible patients, 304 (66%) had Ph- ALL, 270 (89%) of whom were in the primary analysis set (female, 46%; median [range] age at diagnosis, 29 (15-73) years). Of these, 45 (17%) had primary refractory disease, 159 (59%) had relapsed within 12 months of first CR, 49 (18%) had relapsed twice or more, and 17 (6%) had relapsed within 12 months post-HSCT. Baseline characteristics at the time of last salvage therapy among patients without prior HSCT included 195 (72%) with no prior salvage, 45 (17%) with 1 prior salvage, and 6 (2%) with ≥ 2 prior salvage treatments. Prior HSCT (n = 24; 9%) included both autologous (n = 8) and allogeneic (n = 16). Among those with prior HSCT, 18 (7%) had prior salvage, 6 (2%) had 1 prior salvage, and none had ≥ 2 prior salvages.Efficacy data at last salvage are presented in the table. Overall, 31% (84/270; 95% confidence interval [CI], 26%-37%) of patients achieved CR/CRh at last salvage. The median time to CR/CRh was 30 days. Median (range) number of therapies to CR/CRh was 1 (1-3). The occurrence of CR/CRh by line of salvage was 104/254 (41%) for 1st line, 13/55 (24%) for 2nd line, and 1/6 (17%) for 3rd line or later. Median (95% CI) duration of CR/CRh at last salvage was 2.7 (2.0-3.8) months with 57% events among 84 patients who achieved CR/CRh. Among CR/CRh responders, 13 of 16 evaluable patients (81%) achieved a minimal residual disease response. Median (95% CI) OS was 4.4 (3.6-5.1) months, with 54 (20%) deaths among 270 patients. At last salvage, 24/84 (29%) responders subsequently received alloHSCT.Conclusions: In this population of Chinese adults with r/r Ph- ALL treated with currently available salvage chemotherapies, CR/CRh responses were low (31%) and prognosis was poor. The median duration of CR/CRh was short (2.7 months), and the alloHSCT realization rate was low among responders. Thus, new therapies are needed to improve treatment outcomes in Chinese adults with primary refractory or relapsed Ph- ALL. [Display omitted] DisclosuresMeng:Amgen: Employment, Equity Ownership.

Successful Treatment of Peripheral T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: A Large Single-Center Experience

Background: Peripheral T-cell lymphomas (PTCL) are an uncommon heterogenous subset of non-Hodgkin lymphomas for which allogeneic hematopoietic stem cell transplantation (HSCT) is often recommended in the relapsed/refractory setting.Methods: We analyzed overall (OS) and progression-free survival (PFS) in all adults with PTCL who were transplanted 3/2001-12/2014.Results: Patient characteristics are shown in the Table. 65 patients (pts) identified (median age 50.3 years, range 18-70) had a median number of prior treatment regimens of 3 (range 1-8), 42 (65%) were in complete remission (CR) at HSCT (24 in 1st and 18 in > 1st) and 15 in partial remission (PR), 10 (15%) pts had a prior autologous transplant, and the median hematopoietic cell transplant comorbidity index (HCT-CI) score was 2 (range 0-8). Conditioning was myeloablative (MA) in 23, reduced intensity (RIC) in 22, and non-myeloablative (NMA) in 20 pts. Grafts were matched sibling (n=33), mismatched sibling (n=1) matched unrelated donor (MUD) (n=16), mismatched unrelated donor (n=7) or cord blood (n=8). The median day to neutrophil engraftment was 12 (range 9-29), 12 (range 11-23), and 10 (range 8-21) for MA, RIC and NMA respectively. Seventeen (26%) pts had grade II-IV day +100 acute graft-versus-host disease (GvHD) (7 grade II, 7 grade III, 3 grade IV). Eighteen pts (28%) had chronic GvHD. Twenty-one pts have relapsed to date at a median of 3.25 months (range 1.81-71.79). With a median follow-up period for survivors of 41.7 months (range, 6.4-163 months), the OS and PFS rate were 59% and 48% at 2 years (Figure 1). All deaths occurred within 36 months of HSCT. Of 27 pts who have died, 14 died of lymphoma and 13died of HSCT complications. The rate of transplant related mortality (TRM) at 1 year was 17% (95%CI: 7.7-26.1). Causes of death included graft failure (n=1), GvHD (n=7), infection (n=1), pulmonary complications (n=2), cardiac arrhythmia (n=1) and veno-occlusive disease (n=1). There were no differences in TRM according to recipient age, HCT-CI, Karnofsky performance status (KPS), number of prior regimens, prior radiation, receipt of a prior autologous transplant, disease status prior to HSCT or conditioning intensity (all p-values NS). PFS was not affected by disease status prior to HSCT. Degree of HLA-match was significantly associated with TRM (p<0.0001). For pts who underwent matched unrelated, matched related or mismatched donor HSCT, cumulative mortality at 6 months was 6%, 9% and 44%, respectively (Figure 2). Seven of 21 pts who relapsed survive to date, median of 63 months post relapse (range 12-153 months) after treatment with chemotherapy only (n = 2), donor lymphocyte infusion (DLI) (n=3), DLI + HSCT (n=1) or a 2nd HSCT (n=1).Conclusions: We present the largest single center series of HSCT in PTCL. This study suggests existence of GvL effects in patients with PTCL regardless of conditioning intensity or depth of remission at HSCT. Mismatched HSCTs were associated with higher TRM; mainly GvHD. Events were not seen beyond 36 months. This data supports the curative potential of HSCT in a patient group with otherwise poor survival.TablePatient CharacteristicsDiseaseType(N)Median(range)AgeMedian(range)HCT-CIRemissionStatusMedian (range) Prior Regimens/N prior autoRegimenIntensity2-yr PFS(95%CI)PTCL NOS (n=15)52 (30-67)3 (0-7)12 CR 3 PR3 (1-6) 17 MA 4 NMA 4 RIC45% (20%-68%)AITL (n=11)52 (30-70)1 (0-8)8 CR 3 PR3 (1-5) 52 MA 4 NMA 5 RIC81% (44%-95%)ALCL (n=5)47 (28-69)1 (0-5)4 CR 1 PR3 (2-8) 22 MA 2 NMA 1 RIC2 DF 24 & 89 mo; 3 TRM by 15 moCTCL (n=10)/ SPTCL (n=4)47.2 (21-61)1 (0-5)6 CR 8 PR3 (2-8) 03 MA 5 NMA 6 RIC43% (17%-66%)ATLL (n=8)50 (34-68)1.5 (0-6)5 CR 3 PR1 (1-6) 02 MA 3 NMA 3 RIC37% (8%-67%)HSTCL (n=7)28 (18-64)1 (0-4)4 CR 2 PR 1 S1 (1-4) 14 MA 1 NMA 2 RIC38% (6%-71%)NK (n=3)42 (24-47)0 (0-1)2 CR 1 PR1 (1-2) 03 MA1 DF 59 mo 1 TRM 1 DiseaseTPLL (n=1)564CR1/0RIC1 DiseaseEATL (n=1)525CR3/1NMADF 24 moPTCL- peripheral T cell lymphoma (TCL); AITL- angioimmunoblastic TCL,; ALCL- anaplastic large cell lymphoma; CTCL- cutaneous TCL; ATLL- adult TCL; SPTCL- subcutaneous panniculitis TCL; HSTCL- hepatosplenic gamma delta TCL; NK- natural killer TCL; TPLL-prolymphocytic TCL; EATL- enteropathy TCL; CR - complete remission; PR - partial remission; S - stable disease; MA- myeloablative; RI- reduced intensity; NMA- non-myeloablative; mo- month; DF Disease-free [Display omitted] [Display omitted] DisclosuresPerales:NMDP: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Astellas: Honoraria; Merck: Honoraria; Takeda: Honoraria.

Absolute Lymphocyte Count Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome

To determine the impact of absolute lymphocyte count (ALC) recovery on clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) and to determine the threshold value of ALC, we conducted a retrospective study of 1109 adult patients who underwent a first allogeneic HSCT from 2003 through 2009, excluding patients who died or relapsed before D30. The median age was 51 years (range: 18-74) with 52% undergoing reduced intensity HSCT and 48% myeloablative intensity HSCT with T-replete PBSC (93.7%) or marrow (6.4%) grafts; 41% receiving HLA-matched related donors, 51% HLA-matched unrelated donors, and 8.5% HLA-mismatched transplantation. The median follow-up time was 6 years (range: 2.5 – 9.8 years). To determine the threshold value, we randomly split the entire cohort into a training set and a validation set in a 1:1 ratio stratified by conditioning intensity, and then applied a restricted cubic spline (RCS) smoothing method to obtain relative hazard estimates of the relationship between ALC at 1 month and log hazard of progression-free survival. Based on this approach, ALC was categorized as low (≤0.2x 109 cells/L) or normal (>0.2x109 cells/L). For patients with low ALC at 1, 2, or 3 months after HSCT, excluding relapse or death prior to each time point to rule out the direct influence of relapse on the ALC, the overall survival (OS) (p≤0.0001) and progression-free survival (PFS) (p≤0.0002) were significantly lower and non-relapse mortality (p≤0.002) was significantly higher compared to patients with ALC >0.2x109 cells/L at each timepoint, but there was no difference in relapse. Since patients with newly low ALC at 2 or 3 months post HSCT had equally poor outcome as those whose ALC was low at 1 month post HSCT, we combined patients who had low ALC at 1, 2 or 3 months post HSCT and compared their outcome to that of patients who had ALC>0.2x109 cells/L at 1, 2, and 3 months after HSCT. The 5-year OS for patients with low ALC was 28% vs 46% for patients without low ALC (p<0.0001); the corresponding 5-year PFS were 21% vs 39%, p<0.0001 and NRM 40% vs 18%, p<0.0001 (Figure A-C). This result was consistent when other prognostic factors, including occurrence of grade II-IV acute GVHD, were adjusted for in multivariable Cox models stratified by conditioning intensity: HR for OS was 1.52 , p≤0.0001; for PFS, 1.42, p=0.0008; and for NRM, 2.4 p<0.0001 for patients with low ALC within 3 months of HSCT. Low ALC was not significantly associated with relapse (HR 1.01, p=0.92) in the multivariable model. Low ALC early after HSCT is an independent risk factor for increased NRM and poor survival independent of grade II-IV acute GVHD. ALC assessment early after HSCT may be useful to identify high-risk patient cohorts that may benefit from additional therapeutic interventions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation Following Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

Introduction: Improvements in the therapeutic options available for adult relapsed/refractory (r/r) B-precursor ALL are required. Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. Based on encouraging clinical data from a small phase 2 study (Topp MS et al. J Clin Oncol. 2014;32(15s): abstract 7005), we conducted a large confirmatory open-label, single-arm, multicenter phase 2 study of blinatumomab in patients with r/r B-precursor ALL. The aim of the present analysis from this phase 2 study was to characterize those patients who proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) after achieving complete remission (CR)/complete remission with partial hematologic recovery (CRh*) with blinatumomab treatment.Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r B-precursor ALL with one of the following negative prognostic factors: primary refractory, 1st relapse within 12 months of 1st remission, relapse within 12 months of HSCT, or ≥2nd salvage. Blinatumomab was given by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was CR/CRh* within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), HSCT realization rate, 100-day mortality following HSCT, and adverse events.Results: 189 patients with a median age (range) of 39 (18‒79) years were enrolled and received blinatumomab for a median (range) of 2 (1‒5) cycles. At enrollment, 74 (39%) patients had received ≥2 prior salvage therapies, 64 (34%) had received prior HSCT, and 105 (56%) had ≥75% bone marrow blasts.43% (81/189) of patients achieved CR/CRh* within 2 cycles, with similar rates of remission observed in both the HSCT-naïve (42%; 52/125) and prior HSCT (45%; 29/64) groups. In total, 32/81 responders (CR, n=28 and CRh*, n=4) underwent HSCT during blinatumomab-induced remission, yielding a transplantation realization rate for blinatumomab responders of 40% (Table 1). 52% (27/52) of the HSCT-naïve patients and 17% (5/29) of patients who had received prior HSCT proceeded to on-study HSCT during blinatumomab-induced remission. These 32 transplants occurred after a median of 2 (1-5) cycles of therapy, with 11 (34%) patients receiving myeloablative conditioning pre-HSCT, 12 (38%) reduced intensity conditioning, and 9 (28%) unknown regimens. Twenty-two (69%) patients used unrelated donors (stem cells derived from blood, n=11; bone marrow, n=6; cord blood, n=5), 7 (22%) used related donors including 6 siblings (blood, n=5; bone marrow, n=1) and 1 haploidentical mother (blood), with 3 (9%) donor types and stem cell sources unknown. Six patients achieving CR/CRh* after 2 cycles of blinatumomab underwent HSCT but were not included in the transplantation realization rate of 40% due to receiving subsequent antineoplastic therapy before HSCT conditioning (Table 1). Among the 43 patients who achieved CR/CRh* within 2 cycles of blinatumomab treatment but never reached HSCT, 20 (47%) had undergone prior HSCT, 7 (16%) were ≥65 years, and 2 (5%) were ≥65 years and had received prior HSCT (Table 1). [Display omitted] At the time of the primary analysis (data cut-off in October 2013), with median follow-up of 9.8 months, median (95% CI) OS for the 189 blinatumomab-treated patients was 6.1 (4.2‒7.5) months. When censoring for HSCT, median OS was 5.1 (4.1‒7.1) months; although the medians are slightly different, the curves with and without HSCT censoring largely overlap. Median RFS was 5.9 months with and without censoring for HSCT. Nine patients died at any time after HSCT, with 5 deaths due to infection, 3 due to disease progression, and 1 due to graft-versus-host disease (GvHD). Three of these deaths (2 infections and 1 GvHD) were within 100 days of HSCT. The 100-day post-HSCT mortality rate was 11%.Summary: This large phase 2 study demonstrated antileukemia activity of single-agent blinatumomab in heavily pretreated or aggressive r/r ALL, irrespective of prior HSCT. The data suggest that blinatumomab enables patients to reach HSCT, with 11% 100-day mortality post-HSCT. Two-thirds of patients who did not reach HSCT after responding to blinatumomab were either ≥65 years old or had received prior HSCT. Longer follow-up is required to assess the role of HSCT in patients achieving CR/CRh* after treatment with blinatumomab. DisclosuresStein:Amgen Inc.: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Topp:Amgen Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Goekbuget:Amgen Inc.: Consultancy, Honoraria, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria. Dombret:Amgen Inc.: Honoraria, Research Funding. Larson:Amgen Inc.: Consultancy, Research Funding. Rambaldi:Amgen Inc.: Consultancy. Zugmaier:Amgen Reseach (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Jia:Amgen Inc.: Employment, Equity Ownership. Maniar:Amgen Inc.: Employment, Equity Ownership. Huber:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment, Equity Ownership, Related to blinatumomab Patents & Royalties. Kantarjian:Amgen Inc.: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

Changes in renal function in long-term survivors of allogeneic hematopoietic stem-cell transplantation: single-center experience

Renal dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) has been increasingly reported. However, there are few reports on the changes of the estimated glomerular filtration rate (eGFR) in long-term survivors after allogeneic HSCT. The medical records at Seoul St. Mary's Hospital in Korea were reviewed to identify all adult (> 18-years-of-age) patients who had undergone high-dose chemotherapy and allogeneic HSCT between January 2001 and December 2005. Among these patients, those with < 5 years of follow-up and relapse within 5 years after HSCT were excluded. 85 patients were enrolled. The mean follow-up was 76.0 ± 13.5 months. The eGFR recorded 3 months after HSCT was significantly decreased compared with the eGFR recorded before HSCT. Subsequently, early decreased eGFR was maintained during the 60 months after HSCT. Multivariate analysis showed that acute kidney injury (AKI) during HSCT, hypertension (HTN) and eGFR before HSCT was differently associated with changes in eGFR. The eGFR in patients who had AKI decreased significantly at 3 months after HSCT. After 3 months, the eGFR recovered to reach a lower level than in patients without AKI. The level was maintained during the 60 months after HSCT. The eGFR in patients who had low eGFR before HSCT (< 90 ml/min) decreased significantly at 3 months after HSCT, which was also maintained during the 60 months after HSCT. The eGFR in patients who had HTN also decreased significantly at 3 months after HSCT. By contrast, the eGFR decreased consistently and slowly from 3 to 60 months. AKI and low baseline eGFR are associated with early renal dysfunction in patients after HSCT, but are not closely associated with long-term decline in eGFR. In contrast, eGFR in patients with HTN continuously decrease after 3 months of HSCT. Therefore, HTN seems to play a major role in the long-term decline in eGFR. These findings suggest that eGFR at 3 months after HSCT should be monitored closely for all patients who have undergone HSCT. Additionally, long-term follow-up of renal function is needed to prevent further renal damage for patients with HTN.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) is effective therapy for patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) involvement

Abstract Abstract 1358 Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures: No relevant conflicts of interest to declare.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) Is Effective Therapy for Patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) Involvement

AbstractAbstract 1358Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures:No relevant conflicts of interest to declare.

Risk factors for fungal pulmonary infections in hematopoietic stem cell transplantation recipients: the role of iron overload

Fungal pulmonary infections (FPIs) are frequent causes of mortality in hematopoietic stem cell transplantation (HSCT) recipients. Determination of the specific risk factors may improve the prognosis. The aim of this study was to evaluate the risk factors of FPIs due to HSCT. Patient history, physical examination, chest X-rays and the consultation records of the pulmonary disease department which were a part of the routine evaluation before and at first, third, sixth, ninth and twelfth months of HSCT were retrieved in 148 adult HSCT recipients. Results of the high-resolution computed tomography, fiber-optic bronchoscopy and the microbiological data were also included. FPI was diagnosed in 22 patients (14.9%). Multivariate analysis showed that increased ferritin levels (>1000 ng/ml; OR: 3.42, 95% CI 1.03-11.42, P=0.045) and the development of sinusoidal obstruction syndrome (SOS; OR: 5.09, 95% CI 1.53-16.90, P=0.008) were significant risk factors for FPIs. The sensitivity and specificity of ferritin >1000 ng/ml for the prediction of FPIs were 67 and 70%, respectively. There was a positive correlation between the increased risk of FPIs and pretransplantation ferritin levels (r=0.413, P<0.001) and increased ferritin levels and SOS (r=0.331, P<0.001). Increased pretransplantation ferritin levels and development of SOS are predictive factors of FPIs during HSCT.

Improved Outcomes in Diamond Blackfan Anemia Treated Via Stem Cell Transplantation Since the Year 2000.

Abstract 3202Poster Board III-139 BackgroundDiamond Blackfan Anemia (DBA) is a rare disorder characterized by red cell aplasia, congenital anomalies and a predisposition to cancer. Corticosteroids and red cell transfusions are the mainstays of therapy. Hematopoietic stem cell transplantation (HSCT) is curative in DBA, however outcomes have been variable. Nonetheless, preliminary data suggest improvement in HSCT outcomes since the year 2000. PurposeTo compare the degree of HLA compatibility, pre-transplantation iron burden, and survival before and since the year 2000 in sibling and alternative donor HSCT recipients, in order to evaluate if enhanced HLA matching techniques along with improved control of pre-transplant iron burden contribute to improved outcomes. MethodsThe DBA Registry (DBAR) is a comprehensive database of patients with DBA who are enrolled after informed consent is obtained. The patients, their families, and their physicians complete a detailed questionnaire. A review of medical records and telephone interviews are performed to complete and clarify the information provided. Presence of iron burden prior to transplant was determined based upon fulfillment of any of the following criteria: 1) serum ferritin level > 2000 ng/mL within 2 months prior to HSCT, 2) liver iron concentration greater than 8 micrograms per gram, dry weight within 6 months prior to HSCT (measured by MR or biopsy), 3) liver histology from biopsy or autopsy within 6 months of HSCT demonstrating 3+ or greater hemosiderosis or any level of fibrosis. ResultsAs of August 11, 2009, 583 patients have been enrolled in the DBAR, with 55 having undergone an allogeneic sibling or alternative donor HSCT. The median age at HSCT for all patients was 7 years, 8 months; 7 years, 2 months versus 9 years, 8 months for the 32 sibling and 23 alternative donor HSCT, respectively. There were 8 sibling and 13 alternative donor HSCT done prior to the year 2000 compared to 24 and 10 HSCT performed since the year 2000, respectively.Prior to 2000, 8 of 8 sibling HSCT performed were HLA matched, whereas since the year 2000, there were 19 complete and 1 partial HLA matched sibling HSCT done. HLA reports on 4 sibling HSCT were not available for review. There were 5 full and 7 partial matches amongst the alternative donor HSCT done prior to 2000 and 6 full and 2 partial matches since the year 2000. Prior to the year 2000 HLA typing was done by serologic typing alone or by serologic methods for Class I and molecular methods for Class II. HLA typing was done by molecular techniques after the year 2000.Overall survival at 5 years for all patients is 56.6 ± 8.7%; 77.3 ± 8.3% for sibling HSCT and 31.5 ± 12.7% for alternative donor HSCT (p=0.012). For sibling HSCT done prior to 9 years of age survival is 90.0 ± 9.5% and for those older than 9 years of age is 70.0 ± 11.6% (p=0.007). Survival for all patients prior to 2000 and since 2000 is 47.1 ± 11.0% and 72.4 ± 9.3%, respectively (p=0.184). Survival for alternative donor HSCT is 23.1 ± 11.7% prior to 2000 and 85.7 ± 13.2% since 2000 (p=0.047).From data which are available, there are no reported pre-2000 cases of sibling HSCT where absence of iron is documented. Two cases of sibling HSCT pre-2000 had known significant iron overload. One of these patients is the only fatality amongst sibling donor HSCT pre-2000. Post-2000, there were 3 cases of sibling HSCT with significant iron overload and 7 cases of proven absence of iron burden (data on remaining patients are pending). In the alternative donor HSCT pool prior to 2000, 5 of 13 had proven pre-HSCT iron overload and 1 without (data on remaining 7 patients are pending). Since the year 2000, of the alternative donor HSCT, there were 2 proven cases with iron overload and 2 with proven absence of iron burden (data on 6 remaining patients are pending). Overall survival at 5 years for patients without evidence of iron overload is 53.3 ± 18.6% and for those with iron overload pre-transplant is 38.5 ± 23.3 (p=0.97). ConclusionsThe best outcomes for stem cell transplantation in DBA patients occur when using HLA-matched sibling donors in younger patients. There has been a significant improvement in survival with alternative donor SCT since the year 2000 which may be a result of improved HLA matching techniques. There is a trend to improved survival with lower pre-transplant iron burden. DisclosuresNo relevant conflicts of interest to declare.

Early Neurologic Complications After Allogeneic Hematopoietic Stem Cell Transplantation in Children.

Abstract 4314 BackgroundsNeurologic complications after allogeneic hematopoietic stem cell transplantation (HSCT) have not been clearly described, especially in children. MethodsWe analyzed the medical records of 194 consecutive children (median: 7.2 years, range: 6 months-18.4 years) who underwent allogeneic HSCT for malignant or non-malignant hematologic disorders at Asan Medical Center between 1998 and 2009. ResultsDonors were matched siblings in 64, unrelated volunteers in 127 and haploidentical mothers in 3. Twenty-eight children (14%, 95% confidence interval[CI]: 9-19) developed neurologic complications within the first 6 months of HSCT. Calcineurin inhibitor associated-neurotoxicity was the most common neurologic complication (n=14), followed by cerebrovascular events (n=6), thrombotic microangiopathy-associated abnormalities (n=2), hypoxic-ischemic brain injury (n=2), CNS infection (n=1), metabolic encephalopathy (n=1), and events of undetermined cause (n=2). Univariate analysis showed that transplant from unrelated donor, peripheral blood grafts and occurrence of acute GVHD (>grade 1) were associated with significant increased risk of neurologic complications. In multivariate analysis, development of acute GVHD (>grade 1) was identified as an independent risk factor for early neurologic complications. Survival at 1-year was significantly inferior in patients who developed neurologic complications within 6 months of transplant (42% [95% CI: 23-61] versus 82% [95% CI: 76-88], p<0.0001). ConclusionNeurologic complications are significant clinical problems among children receiving HSCT, contributing to early death after transplant. Immediate diagnostic efforts to detect neurologic events are required in patients with clinically suspicious symptoms. Disclosures:No relevant conflicts of interest to declare.

Prognostic implications of declining plasma gelsolin levels after allogeneic stem cell transplantation

The idiopathic pneumonia syndrome (IPS) represents a common and often fatal complication of hematopoietic stem cell transplantation (HSCT). Gelsolin is a highly conserved actin-binding protein normally present in plasma that may serve a basic physiological role in limiting acute lung injury of diverse etiologies. We hypothesized that depletion of circulating gelsolin following HSCT might play a permissive role in the pathogenesis of IPS. Plasma gelsolin levels were measured by immunoblotting in frozen samples obtained weekly from 24 patients undergoing allogeneic HSCT. Patients with and without IPS were similar with respect to age, diagnosis, histocompatibility differences between donor and recipient, and conditioning regimen. Mean gelsolin levels in the 9 patients with rapidly fatal IPS were significantly lower than those in patients without this complication by week 3 after HSCT (101 +/- 61 mg/L versus 221 +/- 54 mg/L; P =.0002). Seven (88%) of the 8 patients with gelsolin levels of less than 100 mg/L in the first month after HSCT died from IPS within 3 months; conversely, gelsolin levels fell to less than 100 mg/L in 7 (78%) of the 9 patients who died from IPS within 3 months of HSCT (P =.0007). These findings suggest that gelsolin levels shortly after allogeneic HSCT can predict the later development of fatal IPS. Gelsolin replacement in selected transplant patients may offer a novel strategy to prevent or reverse IPS.