Type Of Stem Cell Transplantation Research Articles

Outcome of Younger Adults with Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse: A Graall Study

Purpose: Pediatric-like protocols have yielded significant advances in younger adults with Ph-negative ALL. Nonetheless, the 5-year cumulative incidence of relapse was still estimated at 32% in the GRAALL-2003/2005 trials, approximately 25% of the relapses occurring after allogeneic stem cell transplantation (SCT). We report here on the outcome of these relapsing patients.Patients and Methods: Among 880 GRAALL-2003/2005 patients(18-60 years) with Ph-negative ALL in first complete remission (CR1), 264 relapsed. Data were available for 229 of them (151 B-cell precursor [BCP] ALL, 78 T-ALL; 45 standard-risk, 165 high-risk, and 19 unclassified ALL according to the risk classification used in these trials). Relapse site was bone marrow (BM), isolated CNS, combined BM/CNS and other in 181, 20, 17 and 11 patients, respectively. At relapse, median age was 35.7 years (range, 17-63). Median CR1 duration was 10 months (range, 0.5-74), 50 patients (22%) having CR1 > 18 months. Fifty-four patients (24%) had received allogeneic SCT during CR1. First salvage treatments were classified as follows: standard curative therapy, 194 (85%); low-intensity therapy, 21 (9%); allogeneic SCT, 6 (2.5%); and best supportive care (BSC), 8 (3.5%). Post-relapse allogeneic SCT was analyzed as a time-dependent event using Mantel-Byar estimations.Results: A total of 121 patients (53%) achieved CR2, including 100/194 patients after standard salvage, 7/21 patients after low-intensity salvage, and 14 patients after SCT (6 as first salvage, 8 as subsequent salvage after standard salvage failure). Thus, 107/215 patients (50%) treated with standard or low-intensity first salvage achieved CR2 and in multivariable analysis (including age, ALL lineage, ALL risk classification, CR1 duration, prior SCT, relapse site and salvage type), a younger age and a longer CR1 duration were associated with CR2 achievement in these patients. Of note, few patients with t(4;11) BCP-ALL reached CR2 (19%). A total of 77 patients received allogeneic SCT after relapse, including 55 patients in CR2 after standard salvage (52 in CR2 at SCT time), 4 patients in CR2 after low-intensity salvage (all in CR2 at SCT time), the 6 patients transplanted as first salvage (all reaching CR2), and 12 patients transplanted as subsequent salvage (8 reaching CR2). The median time between relapse and SCT was 111 days (range, 5-311). With a median post-relapse follow-up of 3.1 years, post-relapse overall survival (OS) was 19.3% (14-25%) at 2 years and 13.3% (9-19%) at 5 years (median OS, 6.7 months). In landmark analysis, OS was significantly longer in patients who achieved CR2 (HR, 0.19; p<0.001). Post-relapse OS was also longer in patients aged < 45 years old (HR, 0.68; p=0.016), in those with CR1 > 18 months (HR, 0.43; p<0.001), as in those who received SCT after relapse (HR, 0.37; p<0.001). Neither ALL lineage, ALL risk classification, prior SCT, relapse site nor the type of salvage (if excluding the 8 BSC patients) significantly influenced post-relapse OS. A worse OS was nonetheless observed in BCP-ALL patients with t(4;11) (HR, 2.13; p=0.002) or low hypodiploidy / near triploidy (HR, 2.96; p=0.001), as in T-ALL patients with a complex karyotype (HR, 5.55; p<0.001). Neither focal IKZF1 gene deletion nor NOTCH1/FBXW7/RAS/PTENstatus at diagnosis influenced post-relapse outcome, in BCP- and T-ALL patients respectively. In multivariable analysis (including the covariates listed above and not considering the 8 BSC patients), CR1 > 18 months and SCT after relapse were associated with longer OS (HR, 0.49 and 0.39; p=0.001 and <0.001, respectively). Among the 107 patients who reached CR2 after standard or low-intensity salvage, 62 experienced a second relapse and 73 died, including 15 deaths in CR2. In these patients, disease-free survival (DFS) was 29.0% (21-38%) at 2 years and 26.3% (18-35%) at 5 years (median DFS, 10.2 months). Again, CR1 > 18 months and SCT after relapse were the two factors that independently predicted longer DFS (HR, 0.36 and 0.44; p=0.001 and 0.003) and OS (HR, 0.39 and 0.57; p=0.004 and 0.043, respectively) in these patients.Conclusion: Adult patients relapsing after current ALL therapies still retain apoor outcome. Although a minority of them may be cured, especially if CR1 duration exceeds 18 months and if they may receive allogeneic SCT in CR2, new therapies are definitely needed for these patients. DisclosuresNo relevant conflicts of interest to declare.

Favorable Outcomes from Allogeneic and Autologous Stem Cell Transplantation for Patients with Transformed Nonfollicular Indolent Lymphoma

The role of allogeneic (allo-) and autologous stem cell transplantation (auto-SCT) in the management of patients with transformed indolent nonfollicular non-Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n = 47) or auto-SCT (n = 199) across the same institutions and time frame. Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%) small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or platinum-containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%) subsequently underwent allo-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT 40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3-year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P = .38, P = .69, and P = .54, respectively). Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT.

Comparison of restricted mean survival times between treatments based on a stratified Cox model

Abstract Causal inference in survival analysis has been centered on treatment effect assessment with adjustment of covariates. The direct adjustment method is usually employed to find the survival function of a treatment. A Cox model that stratifies the cumulative hazard by treatment is an ideal choice for performing direct adjustment because the treatment effects are allowed to vary over time. A SAS macro was developed to implement comparison of direct adjusted survivals between treatments at a selected time point. The restricted mean survival time can be derived from a direct adjusted survival function. This statistic summarizes the survival outcome of a treatment. Comparison of restricted means provides assessment of treatment effect over a time interval. The first aim of this article was to provide an overview of the restricted mean survival time. The second aim was to introduce a SAS macro that computes the restricted mean survival times from direct adjusted survivals based on a stratified Cox model. Data preparation and macro invocation are illustrated in an analysis of survival data involving three types of stem cell transplants.

Early Evaluation Of Natural Killer Cell Reconstitution Following Unmanipulated Haploidentical Transplantation Compared With HLA-Identical Sibling Transplantation

BackgroundThe main functions of Natural Killer (NK) cells are early protection against viruses or tumour cells and production of cytokines that regulate immune functions. NK cells are the first lymphoid cells to repopulate the marrow after Stem Cell Transplantation (SCT) and reach normal levels within 1 month after transplant. Acquisition of both, inhibiting and activating receptors on developing NK cells is an important step in their functional maturation. Previous studies showed the beneficial effect of NK alloreactivity in prevention of relapse, especially in the setting of haploidentical SCT. The aim of this study is to compare the reconstitution of the NK cell compartment during the first 3 months after unmanipulated haploidentical peripheral blood SCT (Haplo) and HLA-identical sibling peripheral blood SCT (HLA-id). Patients and Methods11 adult patients received SCT (7 Haplo and 4 HLA-id) at Gregorio Marañón Hospital (Madrid-Spain) from November 2012 to April 2013. Conditioning regimen comprised fludarabine, cyclophosphamide and busulfan for Haplo SCT and fludarabine and busulfan or fludaribine and melphalan for HLA-id SCT. Prophylaxis for acute graft-versus-host disease consisted of high dose cyclophosphamide on days +3 and +4, cyclosporine A and mycophenolate mofetil for Haplo and Cyclosporine A and methotrexate for HLA-id. Patient´s characteristics and transplant outcomes are shown in table 1. We analysed reconstitution patterns and phenotype of NK at day +15, +30, +60, and +90 after transplantation by multi-color flow cytometry on FC500 Beckman Coulter® cytometer using the following anti-human monoclonal antibodies: CD3 FITC, CD56 ECD, CD45 PC7, NKG2A PC7, NKp30 PC5, NKp44 PE, Nkp46 PC5, and NKG2D PE (Beckman Coulter®). For comparison between the two groups Mann–Whitney U-test was used. Results2/7 patients who received Haplo SCT died early in the post-transplantation period (day +50 and +66), and were excluded of the analysis because NK cells were not recovered by those days. NK cells reached normal levels by day +30: median 71 cells/µl (21-1089)) after Haplo; median 213.5 cells/µl (113-499) after HLA-id, and remained at high levels through follow up, with no significant differences between the two groups. Similarly to previous studies, a large percentage of NKbrightcells was observed at day +30 after Haplo (median 89% of NK cells (55-97%)), a percentage that tended to decrease at day +60 (30% (7-38%)) and +90 (35% (10-45%)). Interestingly the percentage of NKbright cells after HLA-id SCT at day +30 (median 14.5% of NK cells (6-30%)) compared with Haplo, was significantly lower (p=0.016). This was accompanied by a significantly lower expression of inhibitory receptor NKG2A after HLA-id SCT than after Haplo: 59.5% (50-62%) versus 92.5% (50-62%) at day +30; 54% (38-61%) versus 86% (70-88%) versus at day +60 (p=0.016). Activating receptors NKp44 and NKp30 showed a low expression after both types of SCT throughout the first 3 months after transplantation. By contrast, activating receptor NKp46 levels were significantly higher at day +30 after Haplo than after HLA-id SCT (93% (87-98%) versus 50% (37-51%)) (p=0.016). Finally, high and similar proportions of activating receptor NKG2D were observed in both types of SCT. Figure 1 illustrates the recovery of the NK cell receptor phenotype for each type of SCT. [Display omitted] [Display omitted] ConclusionsOur data showed an early and fast recovery of NK cells after Haplo and HLA-id SCT. However, phenotypic maturation of NK cells appears to be different for each type of transplant. NK cells generated after Haplo exhibit a more immature phenotype, characterized by a higher proportion of NKbright cells, and a higher expression of NKG2A at day +30. Interestingly expression of NKp46 was significantly higher after Haplo than after HLA-id SCT. Other authors have reported cytotoxic activity of these NK cells with high expression of NKp46, suggesting that cytotoxicity may be preserved in these immature NK cells. NKp30, NKG2D and NKp44 expression is less affected by the type of SCT. AcknowledgmentsThis work has been partially supported by Project “Evaluación de la reconstitución inmune después del trasplante haploidéntico de progenitores hemopoyéticos sin depleción T” from Fundación Mutua Madrileña. Disclosures:No relevant conflicts of interest to declare.

Outcomes of autologous or allogeneic stem cell transplantation for non-Hodgkin lymphoma

Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving autologous (auto) SCT (n = 198) or allogeneic (allo) SCT (n = 72) for NHL between the years 2000 and 2010. Five-year overall survival rates for B and T cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T cell lymphoma, respectively). In multivariate analysis, the number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto- and allo-SCT). We conclude that the type of transplantation offered to patients, based on patient selection and disease-related factors, can achieve long-term survival, highlighting the importance of further improvement in disease control and reducing procedure-related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy.

Fungal infections in stem cell transplantation: epidemiology and therapy

Invasive fungal infections (IFIs) are an increasingly important cause of infection-related mortality in stem cell transplantation (SCT). Mortality from IFIs remains high because of diagnostic limitations and has given rise to the concepts of empiric and pre-emptive, as opposed to targeted, antifungal therapy. Data from the 2010 US TRANSET consortium found that Aspergillus (43%) and Candida (28%) were the two most frequently encountered pathogen groups; Zygomycetes and Pneumocystis comprised 8% and 2%, respectively. The frequency of IFIs varies with SCT type with 12 month cumulative incidences highest for matched unrelated SCT and lowest for autologous SCT. Trends in susceptibility to antifungals have identified increasing azole resistance (with cross-resistance) amongst Candid a spp., ampho-tericin B resistance amongst certain moulds and azole resistance in Aspergillus and other moulds. Recommendations for targeted antifungal therapy of yeasts and mould infections of the Infectious Diseases of Society of American, European, and Australian and New Zealand Mycoses Interest Group are similar. Early intervention strategies include empirical therapy which reduces IFIfrequency but has not been shown to reduce mortality and has high costs and drug toxici-ties. Pre-emptive therapy attempts to harness clinical/radiological features in conjunction with fungal biomarkers to detect early disease but its advantage has not been documented.

Hematopoietic stem cell transplantation and rhinosinusitis: The utility of screening sinus computed tomography

To compare prehematopoietic stem cell transplantation (SCT) sinus computed tomography (CT) scans to post-SCT sinus CT scans and to evaluate the relationship between pre-SCT sinus CT scans and the incidence of otolaryngology consultation after SCT. Retrospective chart review. Charts of 228 adult SCT patients from January 2003 to June 2009 with pre-SCT sinus CT scans were reviewed. Data gathered included diagnosis, type of SCT, otolaryngology referral requests, and rhinosinusitis management. Pre- and post-SCT sinus CT scans were scored using the staging system introduced by Lund and Mackay. Two hundred thirty-nine SCTs were performed on the 228 patients included in this study. No disease was identified on 25.1% of pre-SCT CT scans, mild sinus inflammation was identified on 60.7% of scans, 11.3% had moderate inflammation, and 2.9% had severe inflammation. Pre-SCT scans were found to be predictive of post-SCT CT scans. A significant proportion of patients demonstrated worsening of their Lund-Mackay score post-SCT. Pre-SCT CT scores had no predictive ability for otolaryngology consultations. Pre-SCT CT scan scores are associated with post-SCT scan scores; disease severity on CT may worsen following SCT and may be useful for stratifying patients into surgical versus non-surgical candidates. Further study is needed to outline the benefit of sinus surgery in these patients.

Real-world costs of autologous and allogeneic stem cell transplantations for haematological diseases: a multicentre study

Haematopoietic stem cell transplantation (SCT) is an expensive lifesaving procedure, which is increasingly performed in patients with haematological diseases. Developments in the protocol for SCT have resulted in cost estimates that require updating. We aimed to calculate actual costs for SCT and to identify major cost drivers by means of a daily practice cost study. We randomly selected 191 patients, treated at three university hospitals, who underwent an autologous (auto) SCT or allogeneic (allo) SCT in 2007, 2008 or 2009. Allo-SCT included sibling donors, matched unrelated donors (MUD) and umbilical cord blood (UCB). Resource use was collected from the hospital registration systems and medical files. The total costs included selection and harvesting of stem cells, transplantation and 1-year follow-up. The average costs per patient were 45,670 € for auto-SCT and 101,919 € for sibling allo-SCT. The costs of transplantations from unrelated donors were much higher: 171,478 € for allo-SCT-MUD and 254,689 € for allo-SCT-UCB. Hospital inpatient days together with laboratory and other activities were the main cost drivers across all types of SCT. Besides, donor search costs were a large cost component in allo-SCT-sib (18 %) and allo-SCT-MUD (12 %). Real-world costs were above routine reimbursement and appropriate financing is necessary to guarantee the continuation of SCT. The costs calculated in this study provide reliable up-to-date input for cost-effectiveness studies and budget revision.

Regenerating Hearing: Researchers Begin First-Ever Study of Stem Cells to Treat Hearing Loss

Regenerating Hearing: Researchers Begin First-Ever Study of Stem Cells to Treat Hearing Loss

The proarrhythmic risk of cell therapy for cardiovascular diseases

Stem cell therapy is an emerging therapeutic approach for the treatment of cardiovascular diseases. Experimental studies have demonstrated that different types of stem cells, including bone marrow-derived cells, mesenchymal stem cells, skeletal myoblasts, and cardiac progenitor cells and embryonic stem cells, can improve cardiac function after myocardial injuries. Nevertheless, the potential proarrhythmic risk after stem cell transplantation remains a major concern. Several mechanisms, including the immaturity of electrical phenotypes of the transplanted cardiomyocytes, poor cell–cell coupling and cardiac nerve sprouting, may contribute to arrhythmogenic risk after stem cell transplantation. This review summarizes the potential theoretical arrhythmogenic mechanisms associated with different types of stem cells for the treatment of cardiovascular diseases. Nevertheless, current experimental and clinical data on the proarrhythmic risk for different types of stem cell transplantation are limited, and await further experimental and clinical investigation.

Outcomes with Autologous (Auto) and Allogeneic (Allo) Stem Cell Transplantation (SCT) for Relapsed/Refractory Follicular Lymphoma (FL) in the Post-Rituximab Era: A Comparative Analysis From the National Comprehensive Cancer Network (NCCN) Non-Hodgkin's Lymphoma (NHL) Outcomes Database Project,

Abstract 4112 Background:AutoSCT and AlloSCT have both been shown to be effective for the treatment of relapsed/refractory FL. However, outcomes with either modality are not well defined in the post-rituximab era, especially regarding autoSCT. The NCCN NHL Outcomes Database was utilized to examine survival for FL patients (pts) refractory or relapsed after rituximab-based therapy who underwent subsequent autoSCT or alloSCT. Further, prognostic factors were investigated. Methods:The NCCN NHL Outcomes Database is a prospective cohort study collecting comprehensive clinical, treatment, and outcomes data for NHL pts at 7 participating NCCN centers. Among all NHL pts in the database (n=5,395), 1,670 had FL, of whom 240 had SCT during the study observation period of 1/1/00 to 12/31/09 (follow-up through May 2011). Pts were excluded if they 1) did not have relapsed/refractory FL (n=13) or 2) had not received prior rituximab (n=11). In total, 216 pts (autoSCT n=158, alloSCT n=58) were included for analysis. Median follow-up was 2.9 years. Univariate Cox proportional hazards regression was used to assess associations of prognostic factors within each type of SCT for overall survival (OS) and failure free survival (FFS). OS was defined as years from SCT to death; FFS was defined as relapse, transformation, disease progression, or death. Variables with a p <0.20 were entered into a multivariate Cox model within each type of SCT. In a similar fashion, Cox regression was used to assess OS and FFS between type of SCT. Results:There were several notable differences in pt and disease characteristics between SCT modalities. Pts who received autoSCT were significantly older at initial FL diagnosis compared with alloSCT (median 51 vs 46 years, p=0.002) and older at time of SCT (median 55 vs 51 years, p=0.005). However, median time from initial FL diagnosis to SCT was shorter for alloSCT vs autoSCT (3.3 vs 4.1 years, p=0.02). AlloSCT pts received a median of 4 prior therapies vs 3 for the autoSCT cohort (p<0.001). Further, pts who had alloSCT had a higher proportion of resistant disease at time of SCT than autoSCT pts (19% vs 7%, p=0.01), while autoSCT pts were more likely to have grade 3 FL compared with alloSCT (36% vs 9%, p=0.001). There were no comparative differences among gender, race, stage at SCT or performance status. 59% of alloSCT pts had a matched-sibling donor, while 42% had an unrelated donor. The most common conditioning regimens for autoSCT were CBV 50%, BEAM 30%, and TBI-based 16%, while for alloSCT were Flu/Mel 31%, TBI-based 28% (Flu-TBI or Cy-TBI), and Bu/Flu 24%. The cumulative rate of relapse, progression, and/or transformation was 33% for autoSCT pts compared with 16% for alloSCT (p=0.01), while the overall non-relapse mortality (NRM) rate for alloSCT was 33% vs 10% for autoSCT (p<0.0001). There was no difference in FFS between type of SCT (p=0.30) with 3-year FFS of 55% (95%CI 46%-63%) for autoSCT vs 56% (95%CI 42%-70%) for alloSCT (Figure 1). However, OS was significantly different between type of SCT (p<0.001); the 3-year OS was 85% (95%CI 79%-91%) for autoSCT compared with 64% (95%CI 50%-77%) for alloSCT (Figure 2). Factors that predicted survival on univariate analysis for pts who had autoSCT were increasing age (continuous variable, years) and >3 prior therapies, while age > 50 years and resistant disease status at SCT predicted survival for alloSCT. Further, these factors remained significant on Cox regression multivariate analysis (Table 1). Additionally, multivariate analysis including all SCT pts (n=216) was performed to compare survival between autoSCT and alloSCT. After adjusting for age, number of prior therapies, and disease status, alloSCT still showed increased risk of death compared with autoSCT (HR 2.2, 95%CI 1.2–4.1, p=0.01); no significant difference was noted for FFS (p=0.72). [Display omitted] [Display omitted] [Display omitted] Conclusion:To our knowledge, this represents the largest analysis of autoSCT and alloSCT among FL pts relapsed/refractory s/p prior rituximab. Within this multicenter prospective cohort analysis, we identified prognostic factors that predicted survival within autoSCT and alloSCT cohorts. Furthermore, autoSCT and alloSCT were associated with comparable FFS, however including adjustment for competing prognostic factors, OS was improved among pts who had autoSCT. Based on these data, we conclude that autoSCT remains a viable therapy for relapsed/refractory FL in the post-rituximab era. Disclosures:No relevant conflicts of interest to declare.

Frequency and Prognosis of Clonal Chromosomal Abnormalities Following Stem Cell Transplantation (SCT) in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Abstract 4897 Objective.To study the frequency, type and prognostic significance of clonal chromosomal abnormalities following SCT in patients with AML and MDS. Patients and methods.One hundred thirty patients were studied between 2000 and 2010. Karyotypes were analysed by G-banded chromosomes obtained from 24 hours bone marrow cultures, and were described according to ISCN 2009. Results.Clonal abnormalities were observed in 36/130 patients (28%) with a median follow-up was 11 months (range 3–131). Initial diagnosis (OMS 2008): AML with maduration (8 patients), acute erythroid leukaemia (4), acute monocytic leukaemia (3), AML with multilineage dysplasia (3), AML with myelodysplasia-related changes (3), AML with inv(16)(p13q22) (2), acute monoblastic leukaemia (2), AML with minimal differentation (2), AML without maduration (1), acute myelomonocytic leukaemia (1), refractory anaemia with excess blasts (4), chronic myelomonocytic leukaemia (2) and refractory cytopenia with multilineage dysplasia (1). Treatment before SCT: idarubicin, cytarabine, etoposide and mitoxantrone (25), idarubicin, cytarabine and etoposide (6), idarubicin, cytarabine, etoposide and gemtuzumab (2), FLAG-ida (2) and azacitidine (1). SCT type: autologous (23 patients), allogeneic of reduced intensity (7), allogenic (4), umbilical cord blood (1) and syngeneic transplant (1). Conditioning regimen: TBI and cyclophosphamide (24 cases), fludarabine and busulfan (7), busulfan and cyclophosphamide (4) and thymoglobulin, thiotepa, fludarabine and busulfan (1). The median time between SCT and the appearance of clonal abnormalities was 6.5 months (range 2–51). At the time of clonal abnormality detection, 32 patients were in cytological and/or clinical relapse and 4 in cytological remission. In 15 cases the initial clone reappeared, 2 showed the initial abnormalities with an acquired abnormality and 19 presented de novo clonal abnormalities (53%). The most frequent clonal chromosomal abnormalities observed were: complex karyotype (22%), estructural abnormalities with afection of chromosomes 1, 4, 6, 7, 10, 11, 12, 16 and 17 (22%), +21 (5%) and +11 (3%). The median survival from the appearance of clonal abnormalities was 2.5 months (range 1–100). There were no differences when we compared the survival of patients with de novo clonal abnormalities with that of patients with initial abnormalities (including those with acquired abnormality). Furtheremore there were no differences when we compared the median survival of relapsed patients with normal Karyotype with that of patients with clonal chromosomal abnormalities following SCT (2.5 months [range 1–25] and 2.5 months [range 1–100] respectively). At the time of the analysis only 1 patients are alive and in complete remission (100 months). Conclusions.1. The appearance of clonal abnormalities following SCT in patients with AML and MDS is frequent and the majority of cases are detected at the time of relapse. Half of cases presented de novo clonal abnormalities and the majority were not related with prior irradiation exposition, alkylating agents neither topoisomerase II inhibitors. The prognosis of patients with acquired clonal abnormalities after SCT is poor. Disclosures:No relevant conflicts of interest to declare.

Long-Term Survival and Quality of Life Assessment After Allogeneic Stem-Cell Transplantation; Comparable Results Following Myeloablative and Reduced-Intensity Conditioning,

Abstract 4096Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients (pts) with various hematological malignancies. SCT is associated with substantial mortality during the first 2 years after SCT whereas after 2 years survival curves often reach a plateau. However, late mortality and late events continue to cause treatment failures through the late post-transplant course. Quality of life (QoL) is increasingly recognized as an important long-term end-point. The pattern of late events and QoL has been reported following myeloablative conditioning (MAC) but is not well defined in the reduced-intensity (RIC) setting. To explore late outcomes we retrospectively analyzed SCT results in a cohort of 726 pts given allogeneic SCT between 1/2000 and 8/2009. Pts meeting standard eligibility criteria were given MAC (n=207) while pts considered at excessive risk for non-relapse mortality (NRM) were given fludarabine based RIC (n=385) or reduced-toxicity myeloablative conditioning (RTC, n=134). 246 pts were alive and disease-free 2 years after SCT. Their median age was 51 years (17–72). Diagnoses included AML/MDS (n=131), ALL (n=24), lymphatic diseases (n=48), CML/MPD (n=29), non-malignant (n=14). Donors were HLA-matched siblings (n=151), unrelated (n=91) or alternative donors (n=4). Conditioning was MAC (n=72), RIC (n=118) or RTC (n=56). At 2 years after SCT, 172 pts had a history of chronic GVHD, graded as moderate-severe (mod-sev) in 44% and 29% of pts after MAC and RIC/RTC, respectively (p=0.03). 68% and 43% of pts were still on immune suppressive therapy (IST) 2 years after SCT, respectively (p=0.001). With a median follow-up of 68 months after SCT (range, 25–140), the probability of pts surviving disease-free 2 years after SCT to remain alive and disease-free for the next 5 years was 84% (95CI, 75–93) and 82% (95CI, 75–89) after MAC and RIC/RTC, respectively (p=NS). There were 35 deaths beyond 2 years, 15 due to relapse and 20 due to NRM. NRM included 9 deaths due to second cancers; 2 due to relapse of a primary malignancy in pts transplanted for therapy related AML, 4 other solid tumors, 3 donor MDS/AML. 9 pts died of chGVHD/infections and 2 of myocardial infarction. In all, the cumulative incidence of late NRM was 7% (4–11), similar after MAC and RIC/RTC. However, more pts in the MAC group died of chGVHD/ infections (6.9% Vs 2.3%, p=0.08), while more pts in the RIC/RTC group died of second cancers (4.6% Vs 1.4%, p=NS). 24 pts relapsed, 25–102 months after SCT, cumulative incidence 11% (7–16); 9% after MAC and 11% after RIC/RTC (p=NS); 15 died, 9 are alive following further therapies. The kinetics of late relapses was similar with MAC and RIC/RTC. Advanced age (>55) and moderate-severe chGVHD were the most significant predicting factors for shortened survival. OS 5 years after the 2-year time-point was 77% and 89%, in the older and younger groups, respectively (p=0.05). OS was 78% and 90% in pts with and without mod-sev chGVHD, respectively (p=0.004). Multivariate analysis confirmed these as independent factors, HR 2.1 (p=0.07) and 2.6 (p=0.006), respectively. The conditioning regimen, disease type and status at SCT and donor type were not predictive. A history of mod-sev chGVHD predicted for NRM, HR 5.2 (p=0.001). Advanced disease status at SCT predicted for relapse risk, HR 2.6 (P=0.004). The cumulative probability of stopping IST by 8 years after MAC and RIC/RTC SCT was 59 and 75%, respectively (p=0.001). For patients who stopped IST the median duration of IST was 30 and 20 months, respectively (p=0.05). QoL was assessed by the EORTC QLQ-C30 questionnaire. Mean QOL score was 69, 66 and 65 after MAC, RIC and RTC, respectively. A low QOL score (20 points below median) was reported by 15%, 14% and 19%, respectively (p=NS). There was no difference in any of the other domains of QoL assessment as well. Multiple regression analysis identified continuous need IST and reporting depression as factors correlated with a low score while a healthy lifestyle (including return to work, physical and sexual activity) and academic education were associated with high score. In conclusion, the pattern of late outcome is similar after MAC and RIC/RTC. Late NRM is similar although chGVHD is less severe and the required duration of IST is shorter after RIC/RTC. This may lead to better QoL. Younger pts who are disease-free 2 years after SCT, particularly those with no mod-sev chGVHD can expect good long-term outcome and relatively good QOL. Disclosures:No relevant conflicts of interest to declare.

Stem Cell Transplantation for Ischemic Stroke

Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in patients with ischemic stroke is lacking. Our objective was to assess the efficacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL; The …

Treatment of Ocular Graft-Versus-Host Disease With Topical Cyclosporine 0.05%

To evaluate the efficacy of topical cyclosporine-A 0.05% (CsA) in the treatment of dry eye syndrome in ocular graft-versus-host disease after bone marrow transplantation (BMT) of hematopoietic stem cells. One-hundred five patients were enrolled in a retrospective, comparative, interventional case series. Eighty-one patients received topical CsA starting 1 month before BMT (treatment group), and 24 patients did not receive CsA until at least 6 months after the transplantation (control group). Mean follow-up time was 17.5 ± 11.0 months (range: 6.0-49.0 months). Clinical history, ocular surface disease index questionnaire, slit-lamp examination, lissamine green and fluorescein staining of the ocular surface, tear breakup time, and Schirmer test with topical anesthesia were obtained to create a composite dry eye-grading score. Dry eye symptoms were significantly more severe in the control group at 3 months, 1 year, and 2 years (P < 0.05). There was no correlation with type of stem cell transplant (related vs. unrelated donor), presenting indication for BMT, or concurrent systemic immunosuppressive medications. Pre-BMT initiation of topical CsA may reduce the inflammatory response in the lacrimal glands that may be responsible for the development of post-BMT keratitis sicca.

Stem cell transplantation for ischemic stroke

Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in ischemic stroke patients is lacking. To assess the efficacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched November 2008). We also contacted individuals active in the field and stem cell manufacturers (last contacted December 2008). We included randomized controlled trials (RCTs) recruiting patients with ischemic stroke, in any phase of the disease, and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as combined functional outcome or disability and dependency) at longer follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections and neoplastic transformation). Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information. We identified three very small RCTs. Two are still awaiting classification because only subgroups of patients could be included in this meta-analysis and additional unpublished data are needed. The third trial randomized 30 patients to intravenous transplantation of autologous mesenchymal stem cell (10 participants) or reference group (20 participants) (five participants, initially randomized to the intervention group, refused the treatment and were allocated to the reference group) and found a statistically non-significant functional improvement in treated patients at longer follow-up. No adverse cell-related events were reported. No large trials of stem cell transplantation have been performed in ischemic stroke patients and it is too early to know whether this intervention can improve functional outcome. Large, well-designed trials are needed.

The Significance of Hepatic Iron Overload in Allogenic Stem Cell Transplant Recipients.

Abstract 4313 IntroductionIron overload has increasingly been recognized as a cause of morbidity and mortality among allogenic hematopoietic stem cell transplant (HSCT) recipients. Estimation of liver iron is considered the gold standard method that reflects the overall body iron burden. AimWe attempted to correlate the severity of liver iron overload to various clinical parameters in allogenic HSCT recipients. MethodsWe studied 49 adult allogenic HSCT recipients who had a minimum of one liver biopsy performed after transplant. All patients had been diagnosed, transplanted and followed up in our institution since 1998. Biopsies were performed due to abnormal liver function tests under the initial clinical suspicion of GVHD with a mean of 185 days (range: 23-844 days) post-transplant. Sections from each biopsy were stained with hematoxylin and eosin, Masson trichome and Perl's iron stains. We used the histological semiquantitative grading of liver iron (grade 0-4), evidence of GVHD (score 0-3) and fibrosis (stage 0-4). Iron overload was defined as a score of 2 and above (correlating with hepatic iron concentration >1.4 mg/g dry weight). Various clinical parameters were also assessed including age, sex, underlying malignancy, number of transfusions, source and type of stem cell transplant, liver function tests, clinical grading of GVHD, significant bacteremia, other infections, survival and cause of death. ResultsIn this cohort, 28 of 49 patients had iron overload. The overall prevalence of iron overload was 57% (95% confidence interval, 42%-71%). Iron overload in 7 of the 49 patients (14%) was the only histological explanation of liver dysfunction. The degree of iron overload was directly correlated to the number of transfusions (r=0.69, p<0.001), serum ferritin (r=0.55, p=0.004) and the development of significant bacteremia (r=0.33, p=0.019). The correlation to the histologic liver-GVHD grade was close to statistical significance (p=0.062). 37 of the 49 patients (76%) died after HSCT at a mean of 677.8 days (range: 52-3821 days) post-transplant. The overall mortality did not correlate statistically to the degree of iron overload. The mortality was higher in patients with high serum bilirubin (direct or total) and increasing clinical degree of acute GVHD. Sixteen patients died secondary to infection (bacterial=15, fungal=1). However, there was no significant evidence of increased risk of infection-related mortality with iron overload (Hazard Ratio = 1.16, 95% CI, 0.76-1.77, p = 0.496). ConclusionIron overload is a common adverse effect of allogenic HSCT (57% prevalence). Iron overload occurred in some of our patients after as few as 10 red blood cell units. In this cohort, iron overload statistically correlated to the number of transfusions, development of significant bacteremia and clinical acute GVHD. We did not find a statistically significant association with mortality, likely due to our small sample size and complex clinical picture. Iron overload was the only histological explanation of abnormal liver functions in 14% of our patients. More studies are needed to determine the impact of iron overload in long-term morbidity and mortality in allogenic transplant patients. Disclosures:No relevant conflicts of interest to declare.

Long-Term Survival and Late Events After Allogeneic Stem-Cell Transplantation with Reduced-Intensity Conditioning (RIC) for AML and Mds; Comparable Results with Myeloablative Conditioning.

Abstract 518Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients (pts) with AML and MDS. SCT is associated with substantial mortality during the first 2 years after treatment due to relapse and non-relapse causes, whereas after 2 years survival curves often reach a plateau. However, late mortality and late events continue to cause treatment failures through the late post-transplant course. The pattern of late events has been reported following myeloablative conditioning (MAC) but is not well defined in the RIC setting. To explore late outcomes we retrospectively analyzed SCT results in a cohort of 298 pts with AML/MDS given allogeneic SCT with various regimens. As a general role, pts meeting standard eligibility criteria were given MAC, consisting of high dose intravenous busulfan (Bu) and cyclophosphamide (BuCy). Pts considered at excessive risk for non-relapse mortality (NRM), mostly due to advanced age, were given a reduced toxicity regimen such as fludarabine with high-dose Bu (FB4) or treosulfan (FT) or a RIC regimen of fludarabine and reduced doses of Bu (FB2). The 2-year and 5-year overall survival (OS) for this cohort was 48% (95CI, 42-54) and 38% (95CI, 31-44), respectively. We identified 93 pts who were alive and leukemia-free 2 years after SCT. The median age at SCT was 52 years (17-72), 52 male, 41 female. The donors were HLA-matched siblings (n=57) or unrelated donors (n=36. The conditioning regimen was FB2 (n=28), FB4 (n=21, FT (n=15) or BuCy (n=29). At the 2-year time-point, 28 pts had a history of acute GVHD, 68 had a history of chronic GVHD, 43 had active chronic GVHD which still required immune suppressive therapy (IST) in 37. Among pts surviving leukemia-free 2 years after SCT, the probability of remaining alive and leukemia-free, for the next 5 years, was 81% (95CI, 71-91) and 79% (95CI, 69-88), respectively. The probability of OS was 75%, 84%, 92% and 79%, after the various regimens, respectively (p=NS). There were 14 deaths beyond 2 years, 8 deaths due to relapse and 6 due to NRM. NRM included 3 deaths due to solid cancers, 2 due to breast cancer (both in pts transplanted for therapy related AML relapsing with the primary malignancy) and one due to colon cancer. There were 3 additional secondary cancers; breast cancer, squamous cell skin cancer and Kaposi sarcoma (1 pt each; all currently alive). Two pts died of myocardial infarction and one of chronic GVHD. In all, the cumulative incidence of late NRM was 10% (4-24). Interestingly, unlike the early post-transplant period, with current supportive care regimens, late deaths from GVHD and infections are rare. Twelve pts relapsed, 24-59 months after SCT, cumulative incidence 12% (6-23); 8 died, 4 are alive following further therapies, 3 long-term. The kinetics of late relapses was similar with MAC and RIC. Advanced age (>50) was the most significant predicting factor for shortened survival. OS was 64% and 92%, in the older and younger groups, respectively (p=0.03). All deaths due to NRM, and all secondary cancers occurred in the older group (p=0.01). Multivariate analysis (MVA) identified advanced age as the only independent predicting factor for OS; HR 3.1 (1-11.3). The conditioning regimen, disease status at SCT and donor type were not predictive. A history of acute or chronic GVHD predicted improved leukemia-free survival. Age was the most important predicting factor for NRM Active chronic GVHD was the most important factor predicting for reduced relapse risk. The cumulative probability of stopping IST by 7 years post SCT, for the entire cohort, was 73% (63-82). This probability was related to the conditioning regimen and was 80%,76%,80% and 63%, after FB2,FB4,FT and BuCy, respectively (p=0.06 for BuCy versus others). MVA identified conditioning with BuCy (HR 1.8, p=0.06) and male gender (HR 1.7, p=0.04) as predicting for prolonged need for IST. Among the 37 pts who were still on IST 2 years after SCT, the cumulative probability of stopping IST during the following 5 years was only 35%. It was higher in younger pts (59% Vs 15%, p=0.05) and in pts given FB2 (42% Vs. 31%, p=NS). In conclusion the pattern of late outcome is similar after MAC and RIC. Younger pts with AML/MDS who are leukemia-free 2 years after SCT can expect a very good outcome, while older pts are at higher risk for NRM and second cancers, which may not always relate directly to SCT. Pts given RIC are more likely to be able to stop IST, which may be associated with a better quality of life. Disclosures:No relevant conflicts of interest to declare.

India’s stem cell research and development perspectives

We find the review article by Au et al. [1] remarkable andtimely. It portrays India’s recent scenario of stem cellresearch and development. We would like to state furtherthat scientists and medical doctors in India also contribute alot for the technical developments in stem cell researchwith a great potential to tackle India’s future health prob-lems. Perhaps, it is time to remember that India, in 2008has completed 25 years of stem cell transplantation (SCT).India’s first allogeneic bone marrow transplantation (BMT)(one type of SCT) was performed on 20 March 1983 atTata Memorial Hospital VK (File No AP 14703). A 9-year-old girl patient was then suffering from the disease of acutemyeloid leukemia (AML). After BMT, she fully recoveredand currently enjoying a married and employed life, whichis an excellent example of cancer cure through SCT inIndia. For several life-threatening diseases, the SCT prac-tice appears to be a life saving procedure. In India, over20 million carriers and 10,000 children are born each yearwith thalassemia major. Allogeneic SCT is the only curefor thalassemia major, and is cost-effective compared toconventional blood transfusions and iron chelation therapy.The major portion of BMT for thalassemia has been per-formed by the Christian Medical College (CMC) inVellore, south India [2]. In this hospital, 626 transplantshave been performed in 595 patients between October 1986and December 2006. More than one transplant had beenperformed in case of 28 patients [3] (Fig. 1). BMT ofthalassemia accounts for a third of these total transplantsduring this period. Chronic myeloid leukemia (CML) canbe treated with drugs like interferon. This disease can alsobe potentially curable with allogeneic SCT. The cost perallogeneic SCT is much less than the cost of interferontherapy added that period of life. The major portion of SCTin CML has carried by Tata Memorial Hospital, Mumbaiand the SCT can treat other diseases like aplastic anemia,Fanconis anemia, most acute leukemias, myelodysplasiaand certain lymphomas (Fig. 1). For these diseases, a totalof 1540 transplants have been performed during September2005 in six different transplantation centers in India [3].The cost of BMT is about USD 20,000 in India’s besthospitals while in developed countries such as the UK andUSA, it would exceed 4–5 times. Similarly, in other Asiancountries, the cost is higher and in Thailand for example,the cost for BMT is USD 62,500. The lower health carecost is currently boosting medical tourism in India whenIndia’s domestic population has crossed 1.15 billion in2008. As a result, the burden of patients in the existing fewtransplantation centers is increasing; therefore, moretransplant centers are urgently needed in major cities acrossIndia.In the UK, the World’s first stem cell bank was estab-lished in 2003 at Hertfordshire, which is being managed bythe National Institute of Biological Standards (NIBSC) andfunded by the Medical Research Council (MRC) and theBiotechnology and Biological Sciences Research Council(BBSRC). Subsequently, stem cell banks were establishedin all continents except Africa, which is yet to open a cordblood bank (Fig. 2). At present, over 100 cord blood bankshave been established globally. Accordingly in India, theReliance life Sciences (RLS), a Reliance group of

Frequency and prognosis of Clonal Chromosomal Abnormalities Following Stem Cell Transplantation (SCT) in Acute Myeloid Leukemia (AML)

Objective. To study the incidence, type and prognostic significance of clonal chromosomal abnormalities following SCT in patients with AML.Patients and methods. From February 2000 to March 2008, 74 patients were studied. Karyotypes were analysed by G-banded chromosomes obtained from 24 hours bone marrow cultures, and were described according to ISCN 2005.Results. Clonal abnormalities were observed in 17/74 patients (23%). Median follow-up was 11 months (range 5–47). Initial diagnosis: AML2 (6 cases), AML5a (3), AML6 (3), AML with inv(16)(p13;q22) (1), AML with multilineage dysplasia (1), AML5b (1), AML1 (1) and AML0 (1). Treatment before SCT: idarubicin, cytarabine and etoposide (16), FLAG-ida (1). All patients presented a normal karyotype at the time of SCT. SCT type: autologous (12 patients), allogeneic (3), allogeneic of reduced intensity (2). Conditioning regimen: TBI and cyclophosphamide (14 cases), busulfan and cyclophosphamide (1), fludarabine and busulfan (2). The median time between SCT and the appearance of clonal abnormalities was 8 months (range 3–36). At the time of clonal abnormality detection, 16 patients were in cytological and/or clinical relapse and 1 in complete remission. In 4 cases the initial clone reappeared, 1 showed the initial abnormalities with an acquired abnormality and 12 presented de novo clonal abnormalities. The median survival from the appearance of clonal abnormalities was 2 months (range 1–40). At the time of the analysis all patients had died.Conclusions.The appearance of clonal abnormalities following SCT in patients with AML is frequent.Time between SCT and the appearance of clonal abnormalities is short.The majority of patients presented de novo clonal abnormalities with cytological and/or clinical relapse and poor prognosis.