Hematopoietic Cell Transplantation For Hematologic Malignancies Research Articles

Immune Reconstitution Following TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients

TCRαβ/CD19-depleted HCT has been used with excellent outcomes in pediatric patients with hematologic malignancies, and several studies have demonstrated rapid immune reconstitution in the nonmalignant setting. However, immune recovery following TCRαβ/CD19-depleted hematopoietic cell transplantation (HCT) for malignancy remains incompletely elucidated. Furthermore, the majority of studies to date have used haploidentical and matched unrelated donors. Here we report results of immune reconstitution following TCRαβ/CD19-depleted HCT for hematologic malignancy in 51 pediatric patients with hematologic malignancies, the majority of whom received grafts from unrelated donors. Grafts were from matched unrelated (n = 20), mismatched unrelated (n = 20), and haploidentical (n = 11) donors. The median CD34+ cell dose was 10.2 × 106/kg (range, 4.54 to 20 × 106/kg), and the median TCRαβ+ cell dose was 2.53 × 104/kg (range, 0 to 44.9 × 104/kg). Conditioning was myeloablative with either busulfan or total body irradiation, cyclophosphamide, and thiotepa. Thirty-three patients also received rabbit antithymocyte globulin. No prophylactic post-transplantation immune suppression was routinely given. Forty-three patients received rituximab on day +1 for recipient positive Epstein-Barr virus serology.Forty-nine patients (96%) engrafted with a median time to neutrophil recovery of 13 days (range, 8 to 30 days). Thirty-seven patients (73%) are alive at a median follow-up of 25 months (range, 6 to 50 months). Nine patients (18%) developed grade II-IV acute graft-versus-host disease (GVHD), and 5 patients (11%) developed extensive chronic GVHD. Twenty-six patients (51%) experienced viral reactivation. T cell reconstitution was rapid with significant numbers of CD3+, CD4+, and CD8+ T cells present on first assessment at 4 months post-HCT, and significant numbers of naïve CD4+ T cells were present by 8 months post-HCT. Chronic GVHD was associated with delayed T cell recovery; however, T cell reconstitution was not affected by underlying diagnosis, donor source, TCRαβ+ T cell dose, conditioning regimen, or use of antithymocyte globulin. B cell recovery mirrored T cell recovery, and i.v. Ig was discontinued at a median of 8 months (range, 4 to 22 months) post-HCT in patients alive and relapse-free at last follow-up. Immune reconstitution is rapid following TCRαβ/CD19-depleted HCT in pediatric patients with hematologic malignancies. Donor graft source, haploidentical or unrelated, did not affect immune reconstitution. Viral reactivation is common in the first 100 days post-HCT, indicating that improved T cell defense is needed in the early post-HCT period.

Who Enrolls in an Online Cancer Survivorship Program? Reach of the INSPIRE Randomized Controlled Trial for Hematopoietic Cell Transplantation Survivors.

The internet can be a valuable tool in delivering survivorship care to hematopoietic cell transplantation (HCT) cancer survivors. We describe the reach of INSPIRE, an Internet and social media-based randomized controlled trial, to address healthcare and psychosocial needs of HCT survivors. All survivors 2-10 years after HCT for hematologic malignancy or myelodysplasia from 6 transplantation centers in the US were approached by mail and follow-up calls. Eligible participants had access to the Internet, an email address, and did not have active disease in the past 2 years. We used logistic regression to determine characteristics of eligible survivors who were more or less likely to enroll. Of 2578 eligible HCT survivors, 1065 (41%) enrolled in the study. The mean age of enrollees was 56.3 ± 12.6 years (range, 19 to 89 years), 52% were male, and 94% were white. Survivors less likely to enroll included those who were male, age <40 years, and who received an autologous transplant (all P < .001). Compared with white survivors, African Americans were less likely to enroll (P < .001), whereas Native Americans/Alaska Natives were more likely to join the study (P=.03). The reach of the INSPIRE program was broad, including to survivors who traditionally have less access to resources, such as Native Americans/Alaskan Natives and rural residents. Strategies are still needed to improve the enrollment of online studies of survivorship resources for males, young adults, African American, and autologous HCT survivors because their use may improve outcomes.

Vascular Structure and Function in Cancer Survivors after Hematopoietic Stem Cell Transplantation

This study examined the effects of hematopoietic cell transplantation (HCT) and associated preparative regimens on vascular structure and function. Measures of carotid artery stiffness and brachial artery endothelial-dependent dilation were obtained in patients who had survived ≥ 2 years after HCT for hematologic malignancy and were diagnosed at ≤21 years. HCT survivors (n = 108) were examined: 66 received total body irradiation (TBI) alone or with a low-dose cranial radiation boost (TBI±LD-CRT), 19 received TBI plus high-dose cranial radiation (TBI+HD-CRT), and 23 received a chemotherapy-only preparative regimen (CHEMO). Siblings (n = 83) were invited to participate as control subjects. Although endothelial-dependent dilation did not differ between siblings and HCT survivors, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, and diameter distensibility were greater in siblings than HCT survivors. Comparing the HCT preparative regimens, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, diameter distensibility, and incremental elastic modulus were significantly lower in the TBI+HD-CRT group compared with siblings or with TBI±LD-CRT and CHEMO treatment groups. Cross-sectional distensibility and diameter compliance were significantly lower in the TBI±LD-CRT group compared with siblings. TBI±LD-CRT and CHEMO groups did not differ from each other in these vascular measures. HCT preparative regimens containing TBI+HD-CRT resulted in greater arterial decrements, indicating increased risk for cardiovascular disease.

Evaluation of Pre-Hematopoietic Cell Transplantation (HCT) Brain MRI and Neurologic Complications of Pediatric Patients Undergoing HCT for Hematologic Malignancies.

Adverse neurologic complications (NC) occur commonly in pediatric patients with hematologic malignancies both pre- and post-allogeneic hematopoietic cell transplant (HCT). Given this known risk, we previously obtained pre-HCT brain magnetic resonance imaging (MRI) to document baseline abnormalities but utility of this and findings are not well described. This study aimed to ( a) determine the prevalence and risk factors for abnormal brain MRI and ( b) determine prevalence and risk factors for development of new NC during and 2 years post-HCT. Retrospective chart review included 102 patients with hematologic malignancies who underwent allogeneic HCT between 2000 and 2009 at University of California San Francisco (UCSF) Children's Hospital and included standard HCT data, brain MRI reports, and NC and symptoms pre- and post-HCT. Forty-three percent of patients had abnormal findings on pre-MRI, most commonly nonspecific white matter changes. Neurologic symptoms pre-HCT was the only significant risk factor for abnormal MRI. Eleven patients (11%) developed post-HCT NC. Non-Caucasian race was the only significant risk factor for new NC. Although abnormal pre-HCT brain MRI is common, these findings are not predictive of subsequent NC post-HCT. Therefore routine surveillance may not be informative for that purpose, particularly when general anesthesia is required, which can have detrimental neurocognitive effects. Etiology of NC in pediatric HCT is likely multifactorial and may include genetic and ethnic predispositions.

Abstract 12011: Vascular Function in Leukemia Survivors After Hematopoietic Cell Transplantation

Introduction: Previously, we have documented the effects of radiation and/or chemotherapy on vascular structure and function in childhood cancer survivors. To date, little is known about the effects on vascular health of the hematopoietic cell transplantation (HCT) preparative regimen (total body irradiation [TBI] and high dose chemotherapy) that often accompanies this treatment. Hypothesis: HCT preparative regimens utilizing TBI would result in a decrement in arterial function in HCT survivors than those that did not utilize TBI. Methods: Measures of carotid artery stiffness (compliance, distensibility) and intima-media thickness (cIMT) were obtained from ultrasound imaging in patients who had survived &gt;2 years after HCT for hematologic malignancy and were diagnosed at age &lt;21 yrs. Siblings (n=122) were invited to participate as controls. A total of 87 HCT survivors were examined; 50 received TBI only, 17 received TBI plus central nervous system irradiation (TBI+CNS); another 20 received a chemotherapy only preparative regimen ([CHEMO], most busulfan + cyclophosphamide). Results: Although cIMT did not differ between siblings and HCT survivors, both carotid cross-sectional compliance (CSD) and carotid diameter distensibility (DD) were greater in siblings than HCT survivors (Table). Comparing the different HCT preparative regimens, cIMT did not differ significantly between siblings and the three preparative regimen groups. However, both CSD and DD were significantly lower in TBI+CNS and TBI subjects compared to siblings. Also, carotid incremental elastic modulus (IEM) was significant higher in TBI+CNS than in the TBI only, CHEMO, and sibling groups. Conclusion: These results demonstrate that HCT preparative regimens containing TBI result in greater arterial decrements indicating increased risk for premature atherosclerosis and cardiovascular disease. The addition of CNS radiation to TBI results in further decrements in arterial function.

Comparison of Tacrolimus Versus Cyclosporine with Methotrexate for Immunosuppression after Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia: A CIBMTR Analysis

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for patients with severe aplastic anemia (SAA), but graft-versus-host disease (GVHD) has been a major impediment to success. Cyclosporine (CSP) has been widely used as GVHD prophylaxis after HCT for SAA, while both CSP and tacrolimus (TAC) have been used after HCT for hematological malignancies. The aim of this study was to compare transplant outcomes according to TAC+methotrexate (MTX) vs. CSP+MTX as GVHD prophylaxis after HCT for SAA using large registry data. Patients and methods: The retrospective cohort included 949 patients who had a first allogeneic bone marrow or growth factor-mobilized peripheral blood cell transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) for treatment of SAA using GVHD prophylaxis with MTX in combination with either TAC or CSP from 2001 to 2011. Patients who had ex-vivo T cell depletion were excluded. Study endpoints included grades II-IV acute GVHD, grades III-IV acute GVHD, chronic GVHD, overall mortality, hematopoietic recovery and graft failure. Multivariate Cox regression models were used to evaluate hazard ratios for endpoints with TAC+MTX as compared with CSP+MTX. A stepwise procedure was used in developing models for each outcome, using a P value threshold of 0.05, with GVHD prophylaxis and year of HCT forced in all models. Analyses were performed separately in SIB (n=631) and URD (n=318) recipients. Results: The median age of patients was 19 (range, 0.5 to 70) years. TAC+MTX was used in 62 SIB recipients (10%) and in 120 (38%) URD recipients, and was used more frequently in older patents than in younger patients in both groups. Multivariate analysis showed a decreased risk of overall mortality with TAC+MTX in URD group and an increased probability of neutrophil recovery with TAC+MTX in SIB group, but other outcomes did not differ statistically between TAC and CSP prophylaxis (Table). Center effect was not statistically associated with overall mortality, and results were similar even after adjustment for center effect. Causes of death were similar between CSP and TAC prophylaxis in both SIB and URD recipients. Conclusion: Based on adjusted multivariate analyses, the use of TAC+MTX was associated with a decreased risk of mortality among URD recipients and with earlier neutrophil recovery among SIB recipients. Results showed no statistically significant differences in other outcomes with the 2 prophylaxis regimens, although power was limited by the number of patients treated with TAC. Our results support the use of either prophylaxis regimen for SIB recipients. TAC+MTX may be favored for URD recipients, but the interpretation of the survival difference remains uncertain, since TAC was not associated with a reduction in the risk of GVHD, causes of death were similar between the 2 prophylaxis regimens, and the actual difference in survival was small between the 2 prophylaxis regimens.TableMultivariate analysis of outcomes with TAC+MTX compared to CSP+MTXOutcomeIdentical Sibling (n=631)Unrelated (n=318)HR* (95% CI)PHR* (95% CI)PGrades II-IV acute GVHD1.79 (0.92-3.47)0.091.17 (0.76-1.80)0.48Grades III-IV acute GVHD0.79 (0.19-3.34)0.751.52 (0.81-2.86)0.19Chronic GVHD1.79 (0.92-3.47)0.091.23 (0.80-1.88)0.35Overall mortality1.38 (0.74-2.55)0.310.45 (0.25-0.81)0.008ANC recovery1.47 (1.04-2.08)0.031.29 (0.95-1.75)0.10Platelet recovery1.26 (0.93-1.71)0.130.89 (0.66-1.20)0.44Graft failure1.08 (0.45-2.56)0.870.48 (0.16-1.48)0.20*Adjusted for other covariates. DisclosuresNo relevant conflicts of interest to declare.

Late Relapse After Allogeneic Hematopoietic Cell Transplantation For Hematological Malignancies: A Nationwide Retrospective Study From The Late Complications and Quality-Of-Life Working Group Of The Japan Society For Hematopoietic Cell Transplantation

Background Allogeneic hematopoietic cell transplantation (HCT) is one of the most curative therapeutic modalities for hematological malignancies. Recent advances in availability of stem cell sources, conditioning regimens, managements of graft-versus-host disease (GVHD) and supportive care have improved the outcomes of HCT. But even now, relapse is still the leading cause of treatment failure and some long-term survivors after HCT suffer late relapse of the original disease. To better understand the risk and risk factors of late relapse in HCT recipients, we conducted a nationwide retrospective study of the patients who received first HCT for hematological malignancies in Japan. Patients and Methods The study population included HCT recipients reported to the Japan Society for Hematopoietic Cell Transplantation. From this database, we extracted the data of patients with hematological malignancies who received first HCT between 1974 and 2011. There were 29,479 recipients selected according to this criterion. Then, we excluded 1,192 (4.0%) cases from the study because of missing key variables. Results A total of 28,287 recipients were evaluated in this study. Median age at transplant was 37 years old (range, 0-88), and 41.0% (n=11,605) were female. Underlying diseases were acute lymphoblastic leukemia (ALL) (n=7,300, 25.8%), acute myeloid leukemia (AML) (n=11,526, 40.7%), chronic myelogenous leukemia (CML) (n=3,038, 10.7%), myelodysplastic syndrome (MDS) (n=3,235, 11.4%), malignant lymphoma (ML) (n=2,956, 10.5%) and plasma cell disorder (PCD) (n=232, 0.8%). Type of transplant included bone marrow transplantation (BMT) from HLA-matched or 1 locus serological mismatched (“matched”) related donor (n=8,002, 28.3%), BMT from more than 1 locus-mismatched (“mismatched”) related donor (n=261, 0.9%), BMT from HLA-matched unrelated donor (n=9,074, 32.1%), BMT from HLA-mismatched unrelated donor (n=1,112, 3.9%), peripheral blood stem cell transplantation (PBSCT) from “matched” related donor (n=4,385, 15.5%), PBSCT from “mismatched” related donor (n=467, 1.7%), cord blood transplantation (CBT) from “matched” unrelated donor (n=2,326, 8.2%) and CBT from “mismatched” unrelated donor (n=2,556, 9.0%). Myeloablative conditioning regimens were applied to 77.0% (n=21,773) of recipients and reduced-intensity conditioning regimens to 22.1% (n=6,247). Median follow-up of survivors was 1,934 days (range, 18-11,123). Event-free survival of all cases was 41.8% and cumulative incidence of relapse (RI) of them was 33.1% at 5 years. Disease-free survival (DFS) and RI at 7 years of recipients who had been in remission for 2 years since HCT (“DF2”, n=11,500) were 83.2% and 10.2%. DFS and RI at 10 years of recipients who had been disease-free for 5 years (“DF5”, n=7,093) were 91.5% and 2.9%. In multivariate analysis, disease, disease risk at transplant and patients’ age were powerful (p&lt;1×10-6) significant variables for DFS both of DF2 and DF5. For risk of relapse, disease and disease risk at transplant were powerful (p&lt;1×10-4) significant variables of both DF2 and DF5, but patients’ age and intensity of conditioning regimen were only of DF2. Adjusted for patients’ age, disease risk at transplant, year of transplant, donor-recipient sex match, ABO disparity, type of transplant and intensity of conditioning regimen, acute and chronic GVHD were included as time-dependent covariates in Cox model for relapse. In DF2, grade II-IV acute GVHD was associated with a reduced risk of relapse for patients with ALL (Hazard Ratio 0.75, 95% confidence interval 0.57-0.99, p=0.043) and AML (0.74, 0.57-0.97, p=0.029), and chronic GVHD for those with CML (0.65, 0.47-0.89, p=0.0067) and ML (0.37, 0.20-0.60, p=0.00067). In DF5, grade II-IV acute GVHD significantly reduced risk of relapse for recipients with AML (0.40, 0.18-0.85, p=0.018), and chronic GVHD for those with CML (0.56, 0.34-0.92, p=0.021). Conclusion Recipients of HCT for hematological malignancies who remain in remission for more than 2 or 5 years have favorable long-term survival. Our study demonstrates there are relatively small but persistent risks of relapse and underlying disease and disease risk at transplant are the major risk factors of late relapse. We also show acute and chronic GVHD are associated with a reduced risk of late relapse but the strength of this association differs between underlying diseases. Disclosures: No relevant conflicts of interest to declare.

Bone mineral deficits in recipients of hematopoietic cell transplantation: the impact of young age at transplant

Low bone mineral density (BMD) has been reported in recipients of pediatric hematopoietic cell transplantation (HCT), but it is unclear whether age at HCT plays a role. The objective of this cross-sectional study was to determine if patients treated with HCT before age 10 years have long-term BMD deficits compared to patients transplanted at an older age and to sibling controls. The study included 151 HCT recipients (87 males), age at study 24.7±8.6 years treated with HCT for hematologic malignancies at age 10.9±6.4 years, and 92 healthy sibling controls (49 males), age at study 22.3±8.0 years. Dual-energy x-ray absorptiometry was performed to measure BMD Z-scores for total body (TBMD), lumbar spine (LBMD), and femoral neck (FNBMD, for subjects ≥20 years at study visit). Patients <10 years at HCT had significantly lower TBMD and FNBMD Z-scores (by 0.5 and 0.8 SD, respectively) compared to controls (P=0.003 and P=0.0001, respectively) and patients >18 years at HCT (P=0.04 and P=0.004, respectively) at an average of 14 years after HCT. In conclusion, this study identified young age at transplant as an important risk factor for bone deficits in young adulthood, suggesting that efforts to reduce bone loss should focus on this patient population.

Transforming growth factor-beta gene polymorphisms and acute graft-versus-host disease.

e18013 Background: Despite allele level HLA matching, graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). Differences in minor histocompatibility antigens impact GVHD and HCT outcome via activation of donor T cells that also mediate a graft-versus-leukemia (GVL) effect. Non-HLA determinants, such as immunomodulatory cytokines can promote or protect against GVHD. Certain cytokine gene polymorphisms have been associated with acute GVHD in related and unrelated donor HCT. Methods: 17 patients (pts) who underwent related or unrelated donor HCT for hematologic malignancies and their donors were retrospectively analyzed for polymorphisms in gene sequences for interleukin (IL)-6, IL-10, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β) and interferon gamma (IFN-γ) using SSP-PCR reagents from One Lambda Inc. (Canaga Park, CA, USA). Pts and donors were categorized into low, intermediate or high producers of respective cytokines based on single nucleotide polymorphisms (SNPs) identified by sequence specific primers as per manufacturer’s instructions. Conditioning regimens included tacrolimus/sirolimus or alemtuzumab/cyclosporine. Results: A marginal association was found between development of acute GVHD and donor intermediate producers of TGF-β (p=0.056). None of the other cytokine gene polymorphisms tested showed significant relationships to either acute or chronic GVHD. Of seven pts tested who received alemtuzumab conditioning, only one pt developed GVHD; both pt and donor were high producers of all five cytokine genes tested. Conclusions: These results suggest that TGF-β gene polymorphisms may affect risk of developing acute GVHD following allogeneic HCT. Further study is warranted in larger cohorts with measurement of low, intermediate, and high cytokine producers, as well as evaluation of the interplay of cytokines and alemtuzumab in GVHD.

Patterns of Acute and Chronic Graft-Versus-Host Disease Following ATG-Based Conditioning for Allogeneic Hematopoietic Cell Transplantation

AbstractAbstract 4479 Background:In vivo T-cell depletion with antithymocyte globulin (ATG) is known to decrease the incidence of acute and chronic graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). However, the detailed patterns of GVHD (incidence, severity, timing, and quality) after ATG-based conditioning have not been examined in large patient cohorts, and it is unknown whether they differ from those seen in patients who do not receive ATG during conditioning therapy. Patients and Methods:We analyzed the incidence and characteristics of acute and chronic GVHD, requirements for immunosuppressive therapy (IST) and survival in a cohort of 174 patients who underwent a first HCT for hematologic malignancy with ATG as a part of their conditioning regimen. The median age was 54 years (range 19–76); all but 5 pts received PBSC, and median follow-up of survivors was 16.9 months (range 3–70 months). Donors were matched related in 18% (n=32), matched unrelated in 44% (n=77), and mismatched unrelated in 37% (n=65). Conditioning regimens were myeloablative in 33% (n=57) and reduced intensity in 67% (n=117). Additional GVHD prophylaxis included tacrolimus in all patients combined with either methotrexate (42%) or MMF (58%). Results:The cumulative incidence of grade II-IV and III-IV acute GVHD at 100 days was 34% and 7%, respectively, with the median time of onset at 43 days (range 11–98 days) after transplant. Eleven patients (6.3%) required additional immunosuppressive treatment due to steroid refractory GVHD. Late/persistent acute GVHD without any evidence of chronic occurred in 25% of patients. NIH chronic GVHD developed in 25 patients, with a cumulative incidence of 24.4% at 2 years. Forty four percent of these patients were classified as classic chronic, and 56% as overlap. The onset of chronic GVHD was quiescent in 20 (80%), progressive in 3 (12%), and de-novo in 2 (8%) patients. The global severity was mild in 9 (36%), moderate in 11 (44%) and severe in 5 (20%) cases. The median time of onset for chronic GVHD was 185 days (range 99–763). In a multivariate analysis of factors predictive for development of chronic GVHD, the only factor associated with development of chronic GVHD was prior grade II-IV acute GVHD (HR 2.5, p =.03). The most common diagnostic organ was mouth (n=16), followed by skin (n=8) and eye (n=1). The median number of sites involved during the course of chronic GVHD was 4 (range 1–7), and the median number of systemic immunosuppressive agents for treatment was 2 (range 0–4). Among the 25 chronic GVHD patients, 5 have discontinued immunosuppression at a median time of 13.1 months (range 6–26) since the diagnosis of chronic GVHD. The cumulative incidence of discontinuation of IST was 23% at one year and 50% at two years. Three deaths in the overall cohort were attributed to complications related to acute (n=2) or chronic GVHD (n=1). At 2 years, the overall survival among all 174 pts was 62.4%, cumulative incidence of relapse was 23.1%, and non-relapse mortality was 22.7%. Conclusion:These data from a large, uniformly treated and graded, predominantly peripheral blood stem cell transplant recipient population, confirm that ATG decreases both the incidence and severity of acute and chronic GVHD. In particular, the rate of moderate to severe chronic GVHD is extremely low, resulting in minimal need for tertiary treatment and decreased duration of immunosupression. Disclosures:No relevant conflicts of interest to declare.

Effect of Race on Outcomes After Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia

Abstract 1020Severe aplastic anemia (SAA) is the most common non-malignant indication for hematopoietic cell transplantation (HCT). Although survival after HCT for SAA has improved in recent years, it is not known whether the observed higher survival rates are uniform across racial groups or whether there are differences similar to those seen with HCT for hematologic malignancies. Our primary objective was to compare overall survival after HCT for SAA in patients of African American and Caucasian races. The study population included patients who received HCT in the U.S. between 1990 and 2008. Eighty-four African Americans (cases) and 215 Caucasians (controls) were matched on factors known to be associated with survival after HCT for SAA, including age at HCT (±3 years), donor type (HLA-matched sibling, matched unrelated donor, mismatched unrelated donor), graft type (bone marrow or peripheral blood progenitor cells) and transplant year (±1 year). For 39 cases the match ratio for controls was 1:4, for 14 cases, 1:3, for 22 cases, 1:2 and the remaining 9 cases, 1:1. The median age of cases and controls was 17 years and the median interval from diagnosis to HCT was 3.4 months. Forty-five percent of transplants were from unrelated and 55% from HLA-matched sibling donors. A third of unrelated donor-recipient pairs were HLA-mismatched. Bone marrow was the predominant source of stem cells. The median follow-up of cases and controls was 5 years. In multivariate analysis, risk of overall mortality was higher for African Americans compared to Caucasians, relative risk [RR] 1.75, 95% CI 1.14–2.69, p=0.01. Risks of overall mortality were also higher during the early post-transplant period; odds ratio (OR) 2.42, 95% CI 1.09–5.37, p=0.03) and OR 2.61, 95% CI 1.33–5.47, p=0.005) at 3-months and 1-year post-transplantation, respectively. The 5-year probability of overall survival adjusted for interval from diagnosis to HCT, performance score and conditioning regimen, the other significant variables associated with higher mortality was 58% for African Americans and 73% for Caucasians. The likelihood of neutrophil recovery was similar in both groups (OR 1.03, 95% CI 0.46–2.33, p=0.94). Acute grades II–IV graft-versus-host disease (GVHD) risks did not differ between African Americans and Caucasians (RR 0.81, 95% CI 0.56–1.17, p=0.26). However, chronic GVHD risk was higher for African Americans, although the difference did not reach statistical significance (RR 1.55, 95% CI 0.98–2.44, p=0.06). Thirty-seven (45%) of 82 African Americans died compared to 56 (27%) of 207 Caucasians. The proportion of patients dying with GVHD was higher in African Americans (12 of 37; 32%) than among Caucasians (9 of 56; 16%). Death secondary to organ failure was higher in Caucasians (12 of 56; 26%) compared to African Americans (4 of 37; 11%). There were no differences between African Americans and Caucasian in regards to deaths from graft failure, infection or hemorrhage. These data suggest recent improvements in overall survival rates after HCT for SAA are largely limited to Caucasians. Higher mortality in African Americans may be explained by greater genetic diversity, which renders the identification of donors by high-resolution HLA-typing more challenging, genetic polymorphisms impacting drug metabolism and unmeasured co-morbidities. Novel strategies aimed at lowering acute and chronic GVHD rates are needed to lower GVHD-related deaths. Disclosures:No relevant conflicts of interest to declare.

Decline in Sexual Functioning Over a 3-Year Period after Hematopoietic Cell Transplantation (HCT): Gender-Specific Impact of Total Body Irradiation (TBI) and Chronic Graft-Versus-Host Disease (cGvHD)

Sexual dysfunction is a multidimensional problem caused by both physiologic and psychosocial factors. Yet little is known about the longitudinal trends of sexual functioning in HCT survivors, or the clinical or psychosocial factors associated with decline. Using a longitudinal study design, we administered the Derogatis Interview for Sexual Functioning (DISF-SR), the Global Sexual Satisfaction Index (GSSI), and the City of Hope-QOL instrument at 5 time points to a large cohort of patients undergoing HCT at City of Hope (COH): prior to HCT, at 6m, 1y-, 2y-, and 3y-post-HCT. DISF-SR assessed 5 domains of sexual functioning (Cognition/Fantasy, Arousal, Behavior/Experiences, Orgasm, and Drive/Relationship), and a Total score. GSSI elicited patients' subjective appraisal of sexual satisfaction. The COH-QOL instrument was used to obtain self-reported levels of anxiety, distress, depression, pain, physical strength, and sleep changes, which were converted to composite scores of mental and physical stress. Long-term trends of sexual functions were estimated using the Generalized Estimating Equation. We examined the effects of sociodemographic factors, primary diagnosis, HCT conditioning regimens, disease status at HCT, presence of cGvHD, and composite mental and physical stress levels on the longitudinal trends of DISF-SR, the Total score, and GSSI. The cohort included 312 adults (median age at HCT 48y; 56% males) undergoing autologous (n=175) or allogeneic (n=137) HCT for hematologic malignancies or severe aplastic anemia; 144 patients completed the 3y sexual survey (participation rate at 3 years=75%). GSSI (general sexual satisfaction) declined significantly after HCT (p=0.001) for both men and women, and remained depressed over the 3-y study period, with 40% reporting poor or worse sexual satisfaction level at 3y. There were no significant differences between men and women in terms of general sexual satisfaction level. However, the degree of sexual dysfunction as measured by DISF-SR was worse in women than in men for all domains, and for Total score (p<.001) at all post-HCT time points (Fig. 1A). Furthermore, assessment of DISF-SR scores revealed that while men experienced a persistent decline in satisfaction with Orgasm and Drive/Relationship (p<0.05), women did not demonstrate a significant decline in sexual function in any of the domains post-HCT. Gender-specific multivariate analyses revealed certain subgroups that were more vulnerable to a decline in sexual functions after HCT. Notably, older age (≥40y) (Fig. 1B), being married, and TBI exposure in men (Fig. 1C), and older age (≥30y) (Fig. 1D), being overweight, and greater mental and/or physical stress in women were factors identified as significantly associated with decreased sexual functioning following HCT. Although cGvHD was not directly related to DISF-SR or GSSI, presence of cGvHD was accompanied by worse mental and physical composite scores (p<0.0001). Lower mental and/or physical composite scores in turn were significantly related to lower sexual functions for all domains of DISF-SR, the Total score (Fig. 1E) and GSSI in women (p<0.05). Thus, women may be vulnerable to the effects of cGvHD mediated through mental and/or physical stress, in turn resulting in compromised sexual functions and satisfaction after HCT. This study should inform healthcare providers that patients undergoing HCT require more attention to their sexual QOL within the first year after HCT. Routine inquiry of patients' sexual health should be included in follow-up exams after HCT, especially for those at high risk (i.e. TBI-exposed men and those with cGvHD), with the ability to offer a multidisciplinary approach to managing this distressing complication. [Display omitted]

Hematopoietic Cell Transplantation for Benign Hematological Disorders and Solid Tumors

Allogeneic hematopoietic cell transplantation (HCT) has been successfully used as replacement therapy for patients with aplastic anemia and hemoglobinopathies. Both autologous and allogeneic HCT following high-dose chemotherapy can correct manifestations of autoimmune diseases. The impressive allogeneic graft-versus-tumor effects seen in patients given HCT for hematological malignancies have stimulated trials of allogeneic immunotherapy in patients with otherwise refractory metastatic solid tumors. This session will update the status of HCT in the treatment of benign hematological diseases and solid tumors.In Section I, Dr. Rainer Storb reviews the development of nonmyeloablative conditioning for patients with severe aplastic anemia who have HLA-matched family members. He also describes the results in patients with aplastic anemia given HCT from unrelated donors after failure of responding to immunosuppressive therapy. The importance of leuko-poor and in vitro irradiated blood product transfusions for avoiding graft rejection will be discussed.In Section II, Dr. Guido Lucarelli reviews the status of marrow transplantation for thalassemia major and updates results obtained in children with class I and class II severity of thalassemia. He also describes results of new protocols for class III patients and efforts to extend HCT to thalassemic patients without HLA-matched family members.In Section III, Dr. Peter McSweeney reviews the current status of HCT for severe autoimmune diseases. He summarizes the results of autologous HCT for systemic sclerosis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, and reviews the status of planned Phase III studies for autologous HCT for these diseases in North America and Europe. He also discusses a possible role of allogeneic HCT in the treatment of these diseases.In Section IV, Dr. Richard Childs discusses the development and application of nonmyeloablative HCT as allogeneic immunotherapy for treatment-refractory solid tumors. He reviews the results of pilot clinical trials demonstrating graft-versus-solid tumor effects in a variety of metastatic cancers and describes efforts to characterize the immune cell populations mediating these effects, as well as newer methods to target the donor immune system to the tumor.

Hematopoietic cell transplantation for benign hematological disorders and solid tumors.

Allogeneic hematopoietic cell transplantation (HCT) has been successfully used as replacement therapy for patients with aplastic anemia and hemoglobinopathies. Both autologous and allogeneic HCT following high-dose chemotherapy can correct manifestations of autoimmune diseases. The impressive allogeneic graft-versus-tumor effects seen in patients given HCT for hematological malignancies have stimulated trials of allogeneic immunotherapy in patients with otherwise refractory metastatic solid tumors. This session will update the status of HCT in the treatment of benign hematological diseases and solid tumors. In Section I, Dr. Rainer Storb reviews the development of nonmyeloablative conditioning for patients with severe aplastic anemia who have HLA-matched family members. He also describes the results in patients with aplastic anemia given HCT from unrelated donors after failure of responding to immunosuppressive therapy. The importance of leuko-poor and in vitro irradiated blood product transfusions for avoiding graft rejection will be discussed. In Section II, Dr. Guido Lucarelli reviews the status of marrow transplantation for thalassemia major and updates results obtained in children with class I and class II severity of thalassemia. He also describes results of new protocols for class III patients and efforts to extend HCT to thalassemic patients without HLA-matched family members. In Section III, Dr. Peter McSweeney reviews the current status of HCT for severe autoimmune diseases. He summarizes the results of autologous HCT for systemic sclerosis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, and reviews the status of planned Phase III studies for autologous HCT for these diseases in North America and Europe. He also discusses a possible role of allogeneic HCT in the treatment of these diseases. In Section IV, Dr. Richard Childs discusses the development and application of nonmyeloablative HCT as allogeneic immunotherapy for treatment-refractory solid tumors. He reviews the results of pilot clinical trials demonstrating graft-versus-solid tumor effects in a variety of metastatic cancers and describes efforts to characterize the immune cell populations mediating these effects, as well as newer methods to target the donor immune system to the tumor.