Donor and recipient plasma follistatin levels are associated with acute GvHD in Blood and Marrow Transplant Clinical Trials Network 0402.

Follistatin is an angiogenic factor elevated in the circulation after allogeneic hematopoietic cell transplantation (HCT). Elevations in follistatin plasma concentrations are associated with the onset of and poor survival after acute GvHD (aGvHD). Using data from the Blood and Marrow Transplant Clinical Trials Network 0402 study (n=247), we sought to further quantify the longitudinal associations between plasma follistatin levels in transplant recipients, as well as baseline HCT donor follistatin levels, and allogeneic HCT outcomes. Higher recipient baseline follistatin levels were predictive of development of aGvHD (P=0.04). High donor follistatin levels were also associated with the incidence of aGvHD (P<0.01). Elevated follistatin levels on day 28 were associated with the onset of grade II-IV aGvHD before day 28, higher 1-year non-relapse mortality (NRM) and lower overall survival. In multivariate analyses, individuals with follistatin levels >1088 pg/mL at day 28 had a 4-fold increased risk for NRM (relative risk (RR)=4.3, 95% confidence interval (CI) 1.9-9.9, P<0.01) and a nearly three-fold increased overall risk for mortality (RR=2.8, 95% CI 1.5-5.2, P<0.01). Given the multiple roles of follistatin in tissue inflammation and repair, and the confirmation that this biomarker is predictive of important HCT outcomes, the pathobiology of these relationships need further study.

Low EGF in myeloablative allotransplantation: association with severe acute GvHD in BMT CTN 0402.

Epidermal growth factor (EGF) is a recently described biomarker of acute GvHD (aGvHD). Whether low plasma EGF prior to hematopoietic cell transplantation (HCT) predisposes to the development of aGvHD, or whether EGF levels fall because of severe aGvHD, is unknown. To evaluate this, we tested plasma samples collected at pre-HCT baseline, day +28 and day +100 during the course of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402. We found that baseline EGF plasma concentrations were three-fold lower in HCT recipients compared to donors (24.3 vs 76.0 pg/mL, P<0.01). Ninety-one patients (43%) had a markedly low plasma EGF at pre-HCT baseline, defined as <2.7 pg/mL-an optimal cutpoint associated with development of grade III-IV aGvHD. Patients with these low EGF levels at pre-HCT baseline had a 2.9-fold increased risk of grade III-IV aGvHD by day +100. Patients with low EGF at day +28 after HCT had an increased risk of death (relative risk 2.3, P=0.02) by 1 year due to transplant-related toxicities, especially aGvHD. Our results suggest that very low plasma EGF early in the HCT process may predispose patients to an increased risk of death, potentially due to epithelial damage and limited repair capacity.

Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/ß-catenin pathway and alters immune reconstitution after UCBT.

The outcome of umbilical cord blood transplantation (UCBT) is compromised by low hematopoietic stem cell (HSC) doses leading to prolonged time to engraftment, delayed immunological reconstitution and late memory T-cell skewing. Exposure of UCB to dimethyl-prostaglandin E2 (dmPGE2) increases HSC in vivo. We determined that exposure of UCB T lymphocytes to dmPGE2 modified Wnt signaling resulting in T cell factor (TCF)-mediated transcription. Wnt signaling upregulated interleukin (IL)-7R and IL-2Rß, resulting in enhanced survival mediated by the homeostatic cytokines IL-7 and IL-15. dmPGE2 also induced components of the Wnt pathway and Wnt receptors, thereby priming UCB T cells to receive signals via Wnt ligands in vivo. We observed that the Wnt transcription factor TCF7 and its target EOMES were elevated in the T cells of patients who received PGE2-treated UCBs. Consistent with the role of Wnt/ß-catenin signaling to induce and maintain naive, memory precursors and long-lived central memory CD8(+) cells, these patients also had increased fractions of CD8(+)CD45RO(-)CD62L(+) plus CD8(+)CD45RO(+)CD62L(+) subsets encompassing these T-cell populations. These effects of the PGE2/Wnt/ß-catenin axis may have significant implications for harnessing immunity in the context of UCBT, where impaired immune reconstitution is associated with late memory T-cell skewing.

Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome.

Chronic lymphocytic leukemia (CLL) remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced-intensity (RIC) and 32 with myeloablative conditioning (MAC) between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up of 5.9 years in surviving patients, the 5-year overall survival (OS) for the entire cohort is 63% for RIC regimens and 49% for MAC regimens (P=0.18). The risk of death declined significantly starting in 2004, and we found that 5-year OS for HSCT between 2004 and 2009 was 83% for RIC regimens compared with 47% for MAC regimens (P=0.003). For RIC transplantation, we developed a prognostic model based on predictors of progression-free survival (PFS), specifically remission status, lactate dehydrogenase, comorbidity score and lymphocyte count, and found 5-year PFS to be 83% for Score 0, 63% for Score 1, 24% for Score 2 and 6% for Score ≥3 (P<0.0001). We conclude that RIC HSCT for CLL in the current era is associated with excellent long-term PFS and OS, and, as potentially curative therapy, should be considered early in the disease course of relapsed high-risk CLL patients.

Oral epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation: clinical presentation and treatment outcomes.

Late complications of allogeneic hematopoietic stem cell transplantation (HSCT) include a risk of secondary malignancies. Optimization for early diagnosis and treatment of oral premalignant or malignant lesions requires an assessment of potential predisposing risk factors. The medical records of patients who developed oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) following allogeneic-HSCT were reviewed. Data on HSCT course, chronic graft-versus-host disease (cGVHD), and clinical outcome were recorded; landmark survival was calculated. Twenty-six patients with OED (n=8) and OSCC (n=18) were identified with a median follow-up of 26.5 and 21.5 months, respectively. Premalignant and malignant oral lesions were diagnosed at a median time of 2.5 and 8 years after HSCT, respectively. Chronic GVHD was present in 96% of patients and of these, 96% had oral involvement. Multifocal oral cancer was found in 28% of cases, and localized recurrence was observed in 44% of cases. These results suggest that oral cGVHD may be considered a potential risk factor for the development of OSCC following allogeneic-HSCT. The observation that oral cancers were frequently multifocal and recurred locally suggests that these cancers may be more aggressive. Vigilant follow-up and coordination of care are critical.

(90)Y-ibritumomab tiuxetan followed by reduced-intensity conditioning and allo-SCT in patients with advanced follicular lymphoma.

Reduced-intensity conditioning (RIC) hematopoietic SCT (HSCT) is a potentially curative therapeutic option for patients with advanced follicular lymphoma (FL), but disease relapse remains the most common cause of failure. Radioimmunoconjugates administered before RIC allo-HSCT may enhance cytoreduction and allow more time for GVL effect to develop without the associated toxicity of a myeloablative HSCT. We performed a retrospective study to describe the outcomes of patients with relapsed, refractory or transformed FL who received yttrium-90 ((90)Y)-ibritumomab tiuxetan followed by fludarabine and low-dose BU RIC allogeneic HSCT at the Dana-Farber Cancer Institute between 2006 and 2009, inclusively. Twelve patients were identified with a median age of 55 (40-66) years and a median number of lines of therapy of 5 (2-10). Two patients (17%) had transformed to a more aggressive histology and five (42%) had chemorefractory FL. Cumulative incidences of grade II-IV acute GVHD at 100 days were 17% (±11%) and chronic GVHD at 12 months were 63% (±19%). Two-year non-relapse mortality was 18% (±12%). Two-year OS and PFS were 83% (±11%) and 74% (±13%), respectively. This treatment is associated with favorable outcomes including acceptable rates of GVHD and relapse in advanced FL patients, and warrants prospective studies.

A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome.

BACKGROUND: The prognosis for patients with most forms of T-cell lymphoma is poor. Allogeneic hematopoietic stem-cell transplantation (HSCT) may improve the outcome. PATIENTS AND METHODS: This study examines the outcome of 52 patients who underwent ablative or nonablative allogeneic HSCT for peripheral T-cell lymphoma (PTCL) or advanced mycosis fungoides/Sezary syndrome over a 12-year period at a single institution. We divided the patients into those with predominantly nodal histologies: peripheral T-cell not otherwise specified (PTCL NOS), angioimmunoblastic (AITL), or anaplastic large cell lymphoma, T/null type (systemic) (ALCL), and predominantly extranodal histologies: natural killer (NK)/T cell, enteropathy type, hepatosplenic, subcutaneous panniculitic, mycosis fungoides, or T cell or NK cell other. RESULTS: Median follow-up of survivors is 49 months. Non-relapse mortality and relapse at 3 years was 27% and 43%, respectively. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 21%. The incidence of extensive chronic GVHD at 2 years was 27%. The 3-year progression-free survival was 30%: 45% in patients with predominantly nodal histologies (PTCL NOS, AITL, and ALCL) and 6% in patients with predominantly extranodal histologies (P = 0.016). Overall survival at 3 years was 41% for all patients. CONCLUSION: Allogeneic HSCT can produce long-term remissions in relapsed/refractory T-cell lymphoma, especially those with nodal histologies.

Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis.

The main limitations to umbilical cord blood (UCB) transplantation (UCBT) in adults are delayed engraftment, poor immunological reconstitution and high rates of non-relapse mortality (NRM). Double UCBT (DUCBT) has been used to circumvent the issue of low cell dose, but acute GVHD remains a significant problem. We describe our experience in 32 subjects, who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/antithymocyte globulin and who received sirolimus and tacrolimus to prevent acute GVHD. Engraftment of neutrophils occurred in all patients at a median of 21 days, and platelet engraftment occurred at a median of 42 days. Three subjects had grade II-IV acute GVHD (9.4%) and chronic GVHD occurred in four subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At 2 years, NRM, PFS and OS were 34.4, 31.2 and 53.1%, respectively. As expected, immunologic reconstitution was slow, but PFS and OS were associated with reconstitution of CD4(+) and CD8(+) lymphocyte subsets, suggesting that recovery of adaptive immunity is required for the prevention of infection and relapse after transplantation. In summary, sirolimus and tacrolimus provide excellent GVHD prophylaxis in DUCBT, and this regimen is associated with low NRM after DUCBT.

Outcome of allo-SCT for women with MDS or AML occurring after breast cancer therapy.

Women with breast cancer who receive adjuvant therapy are at risk for developing therapy-related myelodysplastic syndrome (MDS) or AML (tMDS/AML). Patients with tMDS/AML are often referred for consideration of allogeneic hematopoietic SCT (HSCT). However, the outcomes of HSCT in such patients have not been well described. We report a retrospective study of all women who were treated with HSCT for MDS or AML at our institution between 1991 and 2008. We compared the transplantation outcomes for 24 women with a history of breast cancer with those for 271 women with de novo disease. Three-year OS and disease-free survival (DFS) for patients with a history of breast cancer were 41 and 45%, respectively. The cumulative incidences of tMDS/AML relapse and non-relapse mortality (NRM) were 38 and 17%, respectively. Those outcomes were very similar to those of patients with de novo disease. In multivariable analyses, a history of breast cancer had no impact on OS, DFS, relapse or NRM. A significant proportion of women with tAML/MDS after breast cancer treatment experience DFS after HSCT, similar to that of patients with de novo MDS or AML. This justifies consideration of HSCT for selected patients in this setting.

Health psychology and distress after haematopoietic stem cell transplantation.

The purpose of this study of 23 adult haematopoietic stem cell transplantation (HSCT) recipients is to compare the presence of post-transplantation depression disorders by gender and to compare the outcomes among those with and without depressive disorders using a health psychology focus. This cross-sectional pilot study of mid-term survivors took place in hospital outpatient clinic. Main outcome measures are depression disorders, health status (Short Form-12) and health anxiety. Female survivors had a higher rate of depression disorders, but those with treated depressive disorders were similar to those without depression on health-related quality of life and health anxiety. Neither patient age nor time since HSCT was associated with depressive disorders. A health psychology approach may enhance management of HSCT survivorship.

Preinfusion variables predict the predominant unit in the setting of reduced-intensity double cord blood transplantation.

Double cord blood transplantation (DCBT) may overcome the slow hematopoietic recovery and engraftment failure associated with infusion of a single cord blood unit. In DCBT, only one unit typically contributes to long-term hematopoiesis, but little is known about factors affecting cord predominance. As results from a phase I trial suggested that order of infusion may affect cord predominance, we analyzed the effect of preinfusion variables on chimerism patterns of 38 patients enrolled in the initial study and a subsequent phase II trial. All patients were treated with a reduced-intensity conditioning (RIC) regimen of fludarabine, melphalan and thymoglobulin followed by DCBT. By day 100, 66% of patients had hematopoiesis derived from a single cord blood unit. Higher post-thaw total nucleated cell and CD34+ cell dose were associated with cord predominance and in 68% of patients (P=0.03); the predominant cord blood unit was infused first. Only the post-thaw CD34+ cell dose of the predominant unit predicted time to both neutrophil and platelet engraftment. Although based on a small number of patients, our results identify parameters that may affect cord predominance and engraftment in the setting of DCBT following RIC and suggest possible strategies for selecting infusion order for cord blood units.

Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6.

BACKGROUND: Acute limbic encephalitis has been reported in the setting of treatment-related immunosuppression and attributed to human herpesvirus-6 (HHV6) infection. Clinical and laboratory features of the syndrome, however, have not been well characterized. METHODS: We describe the clinical, EEG, MRI, and laboratory features of nine patients with acute limbic encephalitis after allogeneic hematopoietic stem cell transplantation (HSCT). To explore the relationship between HHV6 and this syndrome, we reviewed available CSF HHV6 PCR results from all HSCT patients seen at our center from March 17, 2003, through March 31, 2005. RESULTS: Patients displayed a consistent and distinctive clinical syndrome featuring anterograde amnesia, the syndrome of inappropriate antidiuretic hormone secretion, mild CSF pleocytosis, and temporal EEG abnormalities, often reflecting clinical or subclinical seizures. MRI showed hyperintensities within the uncus, amygdala, entorhinal area, and hippocampus on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences. CSF PCR assays for HHV6 were positive in six of nine patients on initial lumbar puncture. All patients were treated with foscarnet or ganciclovir. Cognitive recovery varied among long-term survivors. The one brain autopsy showed limbic gliosis and profound neuronal loss in amygdala and hippocampus. Among 27 HSCT patients with CSF tested for HHV6 over a 2-year period, positive results occurred only in patients with clinical limbic encephalitis. CONCLUSIONS: Patients undergoing allogeneic hematopoietic stem cell transplantation are at risk for post-transplant acute limbic encephalitis (PALE), a distinct neurologic syndrome. Treatment considerations should include aggressive seizure control and, possibly, antiviral therapy. PALE can be associated with the CSF presence of human herpesvirus-6, but the pathogenic role of the virus requires further exploration.

Lower costs associated with hematopoietic cell transplantation using reduced intensity vs high-dose regimens for hematological malignancy.

We compared inpatient and outpatient costs alongside clinical outcomes associated with hematopoietic cell transplantation between 2000 and 2003 with high-dose regimens (HDCT, n=185) and with reduced intensity regimens (RICT, n=90) from human leukocyte antigen (HLA)-matched donors for patients with hematological malignancies. With a comparable median follow-up of 3 years, long-term clinical outcomes, including cumulative incidence of chronic graft-vs-host disease, disease-free survival and overall survival, were similar between the two groups. In the univariate analysis, median costs for the first 100 days ($104,380 vs $42,149) and 1 year ($128,253 vs $80,499) in the HDCT group were higher than those in the RICT group. Median days of hospitalization are also higher for HDCT recipients (39 vs 21), although the number of outpatient clinic visits for HDCT recipients were fewer compared to that for RICT recipients (16 vs 25) during the first year. Adjusting for patient characteristics, RICT recipients had approximately 16 fewer days of hospitalization and cost $53,030 less than HDCT recipients within the first year after transplantation. Our data suggest that substantially lower costs and fewer days of hospitalization within the first year after RICT procedures can be obtained with no compromise of long-term clinical outcomes compared to HDCT procedures.

Quality of life associated with acute and chronic graft-versus-host disease.

Acute and chronic graft-versus-host diseases (GVHD) are associated with increased morbidity and mortality after hematopoietic stem cell transplantation (HCT). We prospectively measured the quality of life (QOL) of patients undergoing allogeneic transplantation. Ninety-six subjects completed self-assessment surveys before HCT, and at 6 and/or 12 months post-HCT that included the Medical Outcomes Study Short Form 12 (SF12) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale. Eighty-three percent of survivors responded at 6 and 12 months. Physical and mental functioning assessed by the SF12 was not associated with either acute or chronic GVHD. In contrast, the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant was sensitive to occurrence of either acute or chronic GVHD. GVHD is a major determinant of the long-term QOL of survivors. The adverse effects of acute GVHD are detectable with the TOI at 6 months post transplantation after which development of chronic GVHD is the most strongly correlated with worse QOL.

HLA-C mismatch is associated with inferior survival after unrelated donor non-myeloablative hematopoietic stem cell transplantation.

HLA-C matching is an important determinant of outcome after myeloablative unrelated donor (URD) hematopoietic stem cell transplantation. However, its importance in non-myeloablative stem cell transplantation (NST) is not known. We report a retrospective analysis of 111 patients who underwent URD NST, of whom 78 were 10/10 matched at HLA-A, B, C, DRB1, DQB1 and 33 were mismatched at one or more HLA-C antigen/allele (24 HLA-C only; nine HLA-C+other locus mismatch). Patients were conditioned with busulfan (0.8 mg/kg/day i.v. x 4 days) and fludarabine (30 mg/m(2)/day i.v. x 4 days). Graft-versus-host disease prophylaxis included cyclosporine/prednisone- or tacrolimus/mini-methotrexate-based regimens. HLA-C disparity did not impair engraftment. Median marrow donor chimerisms were >or=90% donor at day+30 and +100 in both groups. Overall survival at 2 years was 30% in HLA-C-mismatched and 51% in 10/10-matched patients (P=0.008). In Cox regression, HLA-C mismatch was an independent predictor of death (hazard ratio 1.85, P=0.04). Treatment-related mortality was higher in the HLA-C-mismatched group: 48 versus 16% (P=0.0001). Cumulative relapse incidence was 35% in the HLA-C-mismatched and 55% in the 10/10-matched cohort, P=0.09. HLA-C mismatch is associated with inferior survival after URD NST.

Routine screening for psychosocial distress following hematopoietic stem cell transplantation.

The diagnosis and treatment of cancer is often associated with high levels of psychosocial distress, yet exploration of these issues is rarely included in routine oncologic care. We conducted a pilot study to evaluate the feasibility of screening for psychosocial distress after autologous and allogeneic stem cell transplantation. A total of 80 adults were enrolled in Boston, MA, USA. Subjects completed self-administered assessments prior to hospital admission, at their first clinic visit after hospital discharge, and at 100 days post transplant. Assessments included validated instruments assessing psychosocial distress and quality of life (QOL). Elevated levels of anxiety and/or depression were detected in 55% of those providing pre-transplant assessments and were associated with compromised QOL. Post transplant screening was successfully performed in 69% of subjects and identified that 44% had symptoms of depression, anxiety or post traumatic stress disorder. Pre-transplant distress was associated with detection of distress after transplantation (81 vs 13%, P< 0.0001). In summary, we detected high levels of distress in transplant patients using self-administered tools. Pre-transplant distress appears to be highly predictive of distress post transplant and is a feasible marker to target screening and intervention programs.