Conditioning Hematopoietic Stem Cell Transplantation Research Articles

Total lymphoid irradiation based conditioning for hematopoietic stem cell transplantation in severe aplastic anemia

PurposeTo retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused.Materials and MethodsBetween 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate.ResultsWith a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT.ConclusionIn our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.

Importance of functional evaluation after hematopoietic cell transplantation

Substantial advances in hematopoietic stem cell transplantation (HSCT) have been accomplished in the last three decades(1). For example, reductions in early mortality by 60% and in overall mortality by 41% have been achieved in patients transplanted in Seattle after the introduction of high intensity conditioning between 2003 and 2007 compared to the 1993 to 1997 period(2). According to the Center for International Blood and Marrow Transplant Research (CIBMTR), several thousands of long-term HSCT recipients are surviving worldwide from diseases considered fatal before transplantation. Nonetheless, HSCT can result in several complications resulting in impaired quality of life (QoL). Determinants of overall benefits of HSCT therefore are not limited to the eradication of the original disease and improved survival, but also to impairment of QoL with an impact on functional performance. As a matter of fact, several studies of QoL that evaluated mental and physical function, domestic and vocational role function and family and social interaction have reported impairments in functional performance in both autologous and allogeneic HSCT recipients(3-5). In this issue of the Revista Brasileira de Hematologia e Hemoterapia, Souza et al. describe the evaluation of functional performance before and after myeloablative conditioning HSCT in patients transplanted in one center in Brazil(6). Evaluation of functional performance included gait performance, grip strength, spine mobility and function role in daily activities using the Human Activity Profile (HAP) questionnaire. A significant decline in functional performance was found in both autologous and allogeneic HSCT recipients, including in the two-minute walk test (gait performance), grip strength of both hands, spine mobility (Schober test) and daily activities using the maximum and adapted activity score of the HAP. These findings are consistent with studies of North American HSCT populations(3-5). To the best of my knowledge, this is the first prospective study evaluating functional performance in a Brazilian HSCT population. Decline in functional performance depends on several factors including the presence of chronic graft-versus-host disease(5), but the decline in functional performance can improve 5 years after HSCT(3,4). Findings of the current study need to be considered as preliminary because of the small population studied and the relative short follow up. A larger population and longer follow up are needed to confirm the current study findings, and to determine if the decline in functional capacity will improve or result in further performance limitations over time. The study of Souza et al. demonstrates the feasibility of conducting a prospective study of functional performance in recipients of HSCT in Brazil(6). Moreover, it creates an opportunity to conduct larger studies to evaluate risk factors for poor functional performance in transplant recipients in Brazil and to design future intervention studies aimed at improving functional capacity and performance after HSCT.

Impact of Rapid Lymphocyte and Monocyte Recovery on Overall Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine/Melphalan Conditioning

Abstract 3040We have previously shown that both lymphocyte and monocyte recovery are strongly associated with improved survival post-myeloablative allogeneic hematopoietic stem cell transplant for acute leukemia (Thoma et al, Biology of Blood and Marrow Transplantation, in press). We hypothesized that rapid lymphocyte and monocyte recovery would have a similarly positive impact on overall survival in reduced intensity conditioning (RIC) HSCT with fludarabine/melphalan. To test our hypothesis, we analyzed 118 consecutive patients who underwent allogeneic HSCT with fludarabine/melphalan conditioning for AML (n=49) and MDS/MPN (n=38), ALL (n=7) and other lymphoid malignancies (n=24) at our institution from 2001–2010. The absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) derived from routine complete blood counts were determined longitudinally at days +15, +30, +60, +100 and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC > 0.3 × 10(9) cells/L were strongly associated with improved survival (OS 29.6 months vs. 5.4 months, p=0.006 and 25.3 months vs. 5.1 months, p=0.01 respectively), a pattern that continued through the day +100 evaluation. Multivariate analysis including age, CD34+ cell dose, unrelated vs. related HSCT, presence of aGVHD, remission status, and longitudinal hematologic parameters revealed that day +100 ALC (RR 0.21, 95% CI 0.07–0.66, p= 0.0096) and day +100 AMC (RR 0.41, 95% CI 0.2–0.9, p=0.047) were the only independent predictors of survival in the model. Pairwise correlations showed moderate negative associations between aGVHD and day +60 and day +100 ALC and AMC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort and identified four clusters of patients, clusters A-D. Patient clusters A and C both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters B and D (not reached for A and C vs. 54.9 and 22.3 months, respectively, p<0.001). No patient in cluster D had a day +100 AMC > 0.3 × 10(9) cells/L, and these patients experienced more acute GVHD (p=0.006) and relapse (8 of 14 patients, p=0.002) compared with clusters A, B, and C (p=0.002). 29 patients who were unable to be clustered with this algorithm, predominantly due to early toxic deaths, had a median survival of 6 months. Consistent with previous observations in our myeloablative cohort, both lymphocyte and monocyte recovery are predictive of overall survival post-RIC HSCT. However, compared to the myeloablative cohort, monocyte recovery in this series appears slightly less strongly associated with survival. Our results also extend the observation of improved survival of ALC and AMC recovery post-HSCT to diseases beyond acute leukemia. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Inotuzumab Ozogamicin (IO) Is An Effective Salvage Therapy That Allows for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Remission in Patients with Advanced Acute Lymphoblastic Leukemia (ALL)

Abstract 3102No highly effective salvage therapy exists for patients with relapsed acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody attached to calicheamycin and targets B lymphocytes in early stages of development. A 56% overall response rate was noted in a Phase I study of single agent IO in patients with refractory ALL (Jabbour ASCO 2011), enabling subsequent transplant in remission in a relatively large number of patients. Of note, in the year prior to the availability of IO, we consulted on 13 patients will ALL beyond second remission and transplanted 5 (38%), and after the availability of IO, we consulted on 41 patients and transplanted 27 (67%). Methods: We describe our findings in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) following treatment with IO between June 2010 and May 2011. IO was administered at 1.8 mg/m2 IV every 3 weeks. Results: 19 patients with median age 32 years (range 5–60) received an allogeneic matched sibling (n=6), matched unrelated donor (n=8), mismatched unrelated donor (n=4), or cord blood HSCT (n=1) in complete remission (CR) (n=2), CR without platelet recovery (n=14), and active disease (n=3); 10 patients were MRD negative at time of HSCT as determined by multiparameter flow cytometry. Patients had received 2 (n=3), 3 (n=9), 4 (n=4), 5 (n=2), or 6 (n=1) lines of salvage therapy prior to HSCT, including 3 patients who had received a prior allogeneic HSCT; IO was the last agent in 17 patients (2 patients refractory to IO received other therapy prior to HSCT). Patients received 1 (n=1), 2 (n=9), 3 (n=6), 4 (n=2), or 5 (n=1) courses of IO a median of 35 days (range 18–69) prior to transplant conditioning with busulfan (Bu) and colafarabine (Clo) (n=8), BuClo+ thiotepa (TT) (n=4), fludarabine (Flu) and melphalan (Mel) (n=1), FluMelTT (n=3), or etoposide and total body irradiation (TBI) (n=3); GVHD prophylaxis was tacrolimus-based for all patients, with post-HSCT cyclophosphamide added for patients receiving mismatched unrelated donors. With a median follow-up of 3 months among surviving patients (0.6–8.2), overall and progression-free survival is 59% at 3 months. There were 11 deaths, 6 from relapse, 4 from multi-organ failure involving VOD, and 1 from pneumonia. Transient liver enzyme elevations were noted in all of the patients, with 26% (n=5) patients developing VOD. The development of VOD was associated with greater lines of prior therapy prior to HSCT (3–5 lines prior salvage therapy, including 2 patients who had a prior allo-HSCT) and more intense transplant conditioning regimens (4 of the 5 patients received BuCloTT or FluMelTT). Conclusions: IO is an effective salvage therapy in patients with advanced ALL, allowing more patients to receive HSCT with encouraging response rates. Longer follow-up is needed to more completely assess disease control. Using reduced intensity HSCT conditioning regimens and avoiding multiple lines of prior therapies may result in less hepatic toxicity. Disclosures:O'Brien:Pfizer: Consultancy. Kantarjian:Pfizer: Research Funding.

Nelarabine-Based Salvage Therapy in Adult Patients with T-Cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma (T-ALL/LL) Relapsing After Allogeneic Stem Cell Transplantation: A French Experience on Behalf of the Group for Research in Adult Lymphoblastic Leukemia (GRAAL),

Abstract 4095 Backgroud:The prognosis of patients with T-ALL/LL has been recently re-assessed, based on monitoring of minimal residual disease (MRD) levels and new insights in pathogenesis (NOTCH1 pathway mutations). To date, allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR) remains the standard option in patients identified with a high risk of relapse. In this context, patients relapsing after HSCT represent a very difficult challenge to get a second CR. Nelarabine, a pro-drug of Ara-G, has been associated with a high response rate in relapsing ALL (Gökbuget N et al., Blood 2011), but very few data are available on its efficacy and safety in the post-HSCT setting. Patients: Medical records of 11 T-ALL/LL patients who received nelarabine-based salvage therapy for a relapse after HSCT were retrospectively reviewed. These patients were treated with nelarabine alone (1,5g/m2/day (D) D1, D3, D5, every 28 days) (N=5) or nelarabine associated with hyperfractionated cyclophosphamide (HyperC; N=6). Results: Ten patients had T-ALL and one had T-LL. Median age was 23 years (14–62) at time of diagnosis. Ten patients underwent HSCT in first CR (median time between diagnosis and HSCT: 141 days). HSCT conditioning regimen was myeloablative for 7 patients including Total Body Irradiation for 6 of them (reduced intensity conditioning for 4 patients). Source of stem cells was hematopoietic peripheral blood stem cells in 6 patients, bone marrow in 4 patients and unrelated cord blood in one patient. Four patients received a transplant from an HLA matched sibling donor and 7 from an unrelated donor (HLA-matched 10/10 in 3 patients). GVHD prophylaxis consisted in ciclosporine for all patients, either associated with methotrexate for 8 patients, mycophenolate for 2 patients or alone for one patient. Eight patients presented grade I-II acute GVHD (no patient had grade III-IV). Two patients developed chronic GVHD (1 extensive). Relapse occurred with a median duration of 199 days (119–2099). Six patients were still under immunosuppressive agents, because of slow tapering off or context of GVHD, which was stopped quickly. One patient presented a relapse in the context of cGVHD. Of the 11 patients treated with nelarabine-based salvage therapy, 81% achieved hematological CR within a median delay of 48 days. At one year, disease-free and overall survivals were 56% and 90%, respectively. Eight patients received additional nelarabine consolidation cycles (median, 4 cycles) and 2 CR patients received Donor Lymphocytes Infusion (1 complete molecular CR). One patient presented acute GVHD following nelarabine-based first cycle, requiring immunosuppressive treatment. Main toxicity was neurological (Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events), with 2 patients presenting sensitive neuropathy and cerebellar ataxia. Conclusion: In patients with T-ALL/LL relapsing after allogeneic HSCT, nelarabine-based salvage therapy was well tolerated with 2 neurological complications grade 2 and one acute GVHD. Moreover, this treatment was associated with a very high (81%) response rate with some patients experiencing prolonged remission. Post-HSCT nelarabine maintenance might thus be a valuable option to investigate in high-risk patients, possibly driven by MRD detection. Assessing immune responses in this particular setting could also be of particular interest. Disclosures:Peffault de Latour:Alexion: Consultancy, Research Funding.

Reduced-Intensity Conditioning Stem Cell Transplantation: Comparison of Double Umbilical Cord Blood and Unrelated Donor Grafts

There are little data comparing umbilical cord blood (UBC) and conventional stem cell sources for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT). We performed a retrospective analysis of RIC HCST using double UCB (dUCB) grafts and RIC HSCT using unrelated donor (URD) grafts. The study included 64 dUCB transplantations and 221 URD transplantations performed at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2004 and 2008. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 14.1% for dUCB and 20.3% for URD (P = .32). The 2-year cumulative incidence of chronic GVHD was significantly lower in dUCB compared with URD (21.9% versus 53.9%; P < .0001). The 2-year cumulative incidence of nonrelapse mortality was significantly higher in dUCB (26.9% versus 10.4%; P = .0009). In our analysis, dUCB HSCT and URD HSCT had comparable 3-year overall survival (46% in dUCB and 50% in URD; P = .49) and progression-free survival (30% in dUCB and 40% in URD; P = .47). dUCBT was associated with greater nonrelapse mortality despite less chronic GVHD. Our findings suggest that the use of 2 partially matched UCB units appears to be a suitable alternative for patients undergoing RIC HSCT without an HLA-matched donor.

The Incidence of Veno-Occlusive Disease Following Allogeneic Hematopoietic Stem Cell Transplantation Has Diminished and the Outcome Improved over the Last Decade

The evolution of the incidence, morbidity, and mortality of veno-occlusive disease (VOD) was analyzed in 845 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) performed over 24 years. A total of 117 patients and 73 patients developed VOD following the Seattle and the Baltimore diagnostic criteria, respectively (cumulative incidence 13.8% and 8.8%). The cumulative incidence was significantly higher in the period 1985 to 1996 than in 1997 to 2008 (11.5% vs 6.5%; P= .01). This decline was because of the low incidence of VOD among reduced-intensity conditioning-HSCT (RIC-HSCT) (2.1%) and the reduction among those receiving myeloablative-HSCT from unrelated donors (32.7% vs 10.5%, P = .001). A total of 35 patients had severe VOD (26 with multiorgan failure [MOF]), and 20 died by VOD (cumulative mortality rate 17.3%, Seattle, or 22.5%, Baltimore). The mortality declined since 1997 (from 22% to 9%; P = .06, Seattle, and from 36% to 14%; P= .04, Baltimore), with the introduction of defibrotide being the only relevant change in the management of patients. This occurred even though the severity of VOD was similar in both periods. Among those with MOF, only 2 of 8 (25%) receiving defibrotide died versus 14 of 18 (78%) receiving other treatments (P = .007). Myeloablative conditioning, previous liver disease, poor performance status, and alternative donors were the variables with higher impact on VOD development. In summary, although VOD remains a dreaded early complication of HSCT, technical and therapeutic progress in recent decades have notably reduced its incidence and improved the outcome.

Long-term follow-up of autologous hematopoietic stem cell transplantation for severe refractory Crohn's disease

Background Although new therapeutic strategies have been developed to control Crohn's disease, medical treatment for refractory cases is not able to prevent extensive and/or repeat surgery. Recently, several cases have been reported of successful remission induction in Crohn's disease patients by means of hematopoietic stem cell transplantation (HSCT). Here we report our long-term (4 to 6 years) outcome in three patients. Patients Three patients (two male, one female) with active severe Crohn's disease were planned to undergo autologous HSCT. All patients were intolerant or refractory to conventional therapies, including anti-TNFα antibodies. Patients either refused surgery or surgery was considered not to be a feasible alternative due to the extensive disease involvement of the small intestine. Methods Peripheral blood stem cells were mobilized using a single infusion of cyclophosphamide 4 g/m 2, followed on day 4 by subcutaneous injections with G-CSF 5 μg/kg twice daily until leukapheresis. CD34+ cells were isolated after leukapheresis by magnetic cell sorting. In two of the three patients a second round of stem cell mobilization using G-CSF only was required, either because of low yield or because of insufficient recovery after CD34 selection. Prior to transplantation, immune ablation was achieved using cyclophosphamide 50 mg/kg/day (4 days), antithymocyte globulin 30 mg/kg/day (3 days) and prednisolone 500 mg (3 days). Endoscopy, barium small bowel enteroclysis and MRI enterography were performed. Results All three patients successfully completed stem cell mobilization, and two of them subsequently underwent conditioning and autologous HSCT with CD34+ cell selection. Treatment was well tolerated, with acceptable toxicity. Now, 5 and 6 years post-transplantation, these patients are in remission under treatment. The third patient went into remission after mobilization and therefore she decided not to undergo conditioning and HSCT transplantation. After a successful pregnancy she relapsed two years later. Since then, she suffers from refractory Crohn's disease for which we are now reconsidering conditioning and transplantation. Conclusion Autologous HSCT appears to be safe and can be an alternative strategy for Crohn's disease patients with severe and therapy resistant disease.

Recovery of Ovarian Function and Pregnancy in a Patient With AML After Myeloablative Busulphan-based Conditioning Regimen

We report a rare case of ovarian function recovery and pregnancy after hormone-replacement therapy (HRT) in the acute myeloblastic leukemia (AML) patient in third complete remission received hematopoietic stem cell transplantation (HSCT) with busulphan-based conditioning regimen. Successful engraftment of the donor cells and full donor's chimerism was achieved without the signs of leukemia. One year after HSCT the patient received a course of HRT as a treatment of hypergonadotropic hypogonadism. After 12 months of HRT the recovery of ovarian function was confirmed. Eight years after the HSCT spontaneous pregnancy occurred; heartbeat of the fetus was registered on week 7. Three weeks later a nonsevere vaginal bleeding occurred and the ultrasound examination showed a nondeveloping pregnancy. Genetic examination of the abortion material showed a full triploid genotype (69 XXX). To our knowledge this is a first case of ovarian function restoration and spontaneous pregnancy in a AML patient after multiple courses of high-dose chemotherapy and busulphan-based myeloablative conditioning for HSCT.

Busulfan Dosing in Children with BMIs ≥85% Undergoing HSCT: A New Optimal Strategy

Childhood obesity has more than tripled in the past 30 years. The prevalence of overweight and obese children has also increased in the pediatric cancer setting, causing substantial concern over proper chemotherapeutic dosing in this population. The purpose of this study was to determine if children with an increased body mass index (BMI) have an alteration in busulfan pharmacokinetics during hematopoietic stem cell transplant (HSCT) conditioning. We retrospectively reviewed data on busulfan pharmacokinetics (PK) on HSCT subjects (subjects were part of a prospective study previously reported by our group at Children's Memorial Hospital) to determine appropriateness of dosing. Subjects were divided into appropriate BMI categories (<25th percentile, 25th-85th percentile, ≥ 85th percentile) and busulfan PK dosing was analyzed (test dose, regimen dose, area under the curve [AUC], and clearance). The dosing based on PK test dose data of children with BMI ≥ 85% was compared against the package insert dosing recommendations of using adjusted ideal body weight (AIBW) in obese patients to determine which dosing schema was most accurate. Children with high BMIs had higher AUCs when dosing on actual weight then their normal or low BMI counterparts. This indicates that children with a high BMI require less drug (2.9 mg/kg using actual body weight) to achieve the same AUC as children with normal BMI (4.0 mg/kg) or low BMI (3.6 mg/kg). Using the recommended AIBW dosing schema, 53% of the patients with high BMIs would have had regimen dose AUCs ≥ 20% over/under the target; whereas with the PK test dose method, only 16% of the patients with high BMIs had regimen dose AUCs ≥ 20% over/under the target. PK testing continues to be the gold standard for busulfan dosing in children. Particular vigilance should be paid to PK monitoring in high BMI categories because of the potential risk of imprecise dosing when using the AIBW schema.

Advances in basic and clinical immunology in 2010

Reports in basic and clinical immunology in 2010 reflected the use of state-of-the-art genetic and immunologic tools to characterize the pathogenesis of immunologic diseases and the development of novel therapies directed to these conditions. B-cell biology has been explained in greater detail, significantly with lessons from the genetic defects found in the humoral immunodeficiencies. Therapeutic mAbs are given for an increasing number of indications, such as anti-CD20 antibodies or rituximab, which was initially developed for non-Hodgkin lymphomas and is currently used in diverse autoimmune and inflammatory disorders. The report of an infant with severe combined immunodeficiency (SCID) in Massachusetts detected by means of newborn screening and successfully treated with hematopoietic stem cell transplantation validated recent efforts toward newborn screening for SCID. Improvement of survival outcomes for patients with primary immunodeficiencies treated with hematopoietic stem cell transplantation was demonstrated in a large European cohort, with significant appreciation of the type of donor graft, particularly the use of HLA-matched unrelated donors for patients with non-SCID. Progress in cellular mechanisms of drug hypersensitivity included the characterization of nitroso-modified drug metabolites as potent T-cell activators and the identification of the relocation of plasmacytoid dendritic cells from blood to skin as a potential risk factor for reactivation of viral disease.

Gene expression profile of cytokines in patients with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation with reduced conditioning

There are no reliable markers useful to predict the onset or the evolution of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), although several candidate biomarkers have been identified from limited hypothesis-driven studies. In this study we evaluated 14 patients who received a reduced intensity conditioning HSCT. Seven patients had cGVHD, whereas 7 never developed cGVHD during the period of observation. The expression of 114 cytokines in immunoselected cell populations was explored by microarray analysis and 11 cytokines were selected for further evaluation by real-time PCR. Differential gene expression measurements showed a significant up-regulation for INFγ (interferon, gamma) in CD8+ and for TNFSF3 (tumor necrosis factor superfamily, member 3) and for TNFSF10 (tumor necrosis factor superfamily, member 10) in CD14+ cell population when comparing cGVHD with control samples. The expression levels were significantly decreased for TNFSF10 in CD8+ cell population and for TNFSF12 (tumor necrosis factor superfamily, member 12) and for PDGFβ (platelet-derived growth factor, beta) in CD4+. Our data seem to suggest that different immune populations can play a role in cGVHD pathogenesis and the early detection of gene expression profile in these patients could be useful in the monitoring of GVHD. We hypothesized that PDGFβ down-regulation could represent a negative feedback to compensate for enhanced expression of its receptor recently reported.

Translational Research Efforts in Biomarkers and Biology of Early Transplant-Related Complications

In the time since the first allogeneic hematopoietic stem cell transplantation (HSCT) was performed over 40 years ago, this life-saving procedure has been used increasingly for patients with hematologic, metabolic, and malignant diseases. Despite major advances in our understanding of the immunologic processes (both beneficial and injurious) that are associated with HSCT and improvements in supportive and critical care medicine, successful outcomes are still limited by several serious complications. As such, the establishment of effective therapeutic strategies for these complications will be crucial as increasing numbers of high-risk transplants are performed each year. The development of such approaches is fundamentally dependent upon a basic understanding of pathophysiologic mechanisms of disease and also on our ability to successfully translate these insights back to the bedside. This brief review will highlight breakthroughs in translational research endeavors that have paved the way for the development of novel strategies intended to change the standard of care and optimize outcomes for patients in whom allogeneic HSCT offers the only hope for a cure.

Use of Matched Unrelated Donors Compared with Matched Related Donors Is Associated with Lower Relapse and Superior Progression-Free Survival after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation

As success of reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) relies primarily on graft-versus-leukemia (GVL) activity, increased minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent GVL in RIC HSCT compared to matched related donors (MRD), we retrospectively studied 433 consecutive T-replete 6/6 HLA matched URD (n = 246) and MRD (n = 187) RIC HSCT for hematologic malignancies at our institution. Diseases included: acute myelogenous leukemia (AML) (127), non-Hodgkin lymphoma (NHL) (71), chronic lymphocytic leukemia (CLL) (68), myelodysplastic syndrome (MDS) (64), Hodgkin disease (HD) (40), chronic myeloid leukemia (CML) (25), multiple myeloma (MM) (23), myeloproliferative disorder (MPD) (12), acute lymphoblastic leukemia (ALL) (7), and other leukemia (1). All received uniform fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/mini-methroxate (mini-MTX) or tacrolimus/sirolimus ± mini-MTX. Unrelated donors were younger compared to MRD (median donor age: 33 years versus 52 years, P < .0001), and provided larger CD34(+) products (median CD34(+) cells infused: 8.7 × 10(6)/kg versus 7.5 × 10(6)/kg, P = .002). Distribution of diseases, disease risk, prior transplant, and cytomegalovirus (CMV) status was similar in both cohorts. Cumulative incidence of grade II-IV acute GVHD (at day +180), 2-year chronic GVHD, and 2-year nonrelapse mortality (NRM) were 20% versus 16%, 55% versus 50%, and 8% versus 6% in URD and MRD, respectively (P= NS). Cumulative incidence of relapse at 2 years was lower in URD, 52% versus 65% (P = .005). With median follow-up of 26.5 and 35.8 months, 2-year progression-free survival (PFS) was significantly better in unrelated donor transplants, 39.5% for URD, and 29% for MRD (P = .01). Overall survival (OS) at 2years were 56% for URD versus 50% for MRD (P = .53). In multivariable analysis, URD was associated with a lower risk of relapse (hazard ratio [HR] 0.67, P = .002) and superior PFS (HR 0.69, P = .002). These results suggest that URD is associated with greater GVL activity than MRD, and could have practice changing impact on future donor selection in RIC HSCT.

Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Low Grade Non Hodgkin's Lymphoma: Preliminary Results at Hospital De CliÃŒnicas De Porto Alegre (HCPA), Porto Alegre, RS, Brazil.

AbstractAbstract 4557 INTRODUCTION:Advanced low grade non-Hodgkin Lymphomas have many and varied treatment options. For patients with relapsed or refractory disease, outcome following only chemotherapy protocols remains poor. The standard Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) might be an alternative for relapsed low grade non-Hodgkin lymphomas, but its high Transplant Related Mortality (TRM), varying from 24% to 54%, accounts for a lower overall survival in this group. Reduced Intensity Conditioning (RIC) HSCT has been shown to be a good alternative to myeloablative regimens, with lower TRM, Graft versus Lymphoma Effect, and appears to be associated with improved outcome, presenting a 3 years disease free survival and overall survival from 32% to 66% and from 32% to 73%, respectively, depending on factors such as disease stage before transplantation. PATIENTS, METHODS AND RESULTS:Sixteen heavily pretreated patients with low grade non-Hodgkin Lymphoma (NHL) were submitted to RIC HSCT with matched related donors at the Bone Marrow Transplantation Unit at HCPA between the period of September 2002 to October 2009. The mean age was 43 years and were 7 patients male and 9 female. Fifty percent (8) of the patients had refractory disease pre-HSCT, 43.8% (7) were at third complete remission (CR) and 6.2% (1) at second CR. Median of CD34/kg infused was 10.7 × 106 and the median of days for engraftment was 14.53. Conditioning regimens were Fludarabine + Cyclophosphamide in 3 patients, Fludarabine + Melphalan in 7, Fludarabine + Cyclophosphamide + Rituximab in 2, Fludarabine + Cyclophosphamide + Melphalan in 1, Cyclophosphamide + Total Body Irradiation (TBI) in 1 and Fludarabine + Cyclophosphamide + TBI in 2. Acute Graft versus Host Disease (aGVHD) occurred in 50%, with 37.5% of those were steroids resistant; and 62.5% of the patients evolved to chronic GVHD, with 80% of them classified as extensive. Chimerism from 9 patients was analyzed, and 89% of them were complete. Mean overall survival was 2.95 years; 62.5% of patients were alive within 1 year and 40% within 3 years. TRM was 6.66%. Eight patients died, five of them were transplanted with refractory disease. Only 2 patients died of relapse, 5 of infections and 1 of aGVHD. CONCLUSION:Low grade NHL patients treated at HCPA with RIC HSCT had an overall survival and TRM comparable to the observed at other centers, appearing as a good alternative for this heavily treated group of patients with less toxicity than myeloablative regimens. Disclosures:No relevant conflicts of interest to declare.

Evaluating the Impact of Antithymocyte Globulin on Lung Function at 1 Year after Allogeneic Stem Cell Transplantation

The use of antithymocyte globulin (ATG) in hematopoietic stem cell transplantation (HSCT) conditioning regimens has reduced the incidence of graft-versus-host disease, particularly in its chronic form. The impact of this approach on the prevention of lung dysfunction has not been well characterized, however. We performed a retrospective analysis of pulmonary function in patients who underwent HSCT after conditioning with oral busulfan followed by either cyclophosphamide or fludarabine with or without the addition of ATG. A total of 393 patients were included; 75 patients received ATG, and 318 did not. No differences between the 2 groups were seen in the mean percentage of the predicted values for forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), total lung capacity, and lung CO diffusing capacity at 80 days or 1 year after transplantation. However, the mean value of FEV(1)/FVC ratio at 1 year was higher in the patients who received ATG. The difference in mean change in pulmonary function parameters from baseline to 1 year post-HSCT was statistically nonsignificant for all parameters except FEV(1)/FVC ratio, which demonstrated less decline in the ATG group. The risk of developing severe airflow obstruction or a restrictive pattern was similar in the 2 treatment groups at 1 year post-HSCT. Incorporation of ATG into the HSCT conditioning regimen provided protection against a decline in FEV(1)/FVC ratio but did not decrease the risk of other pulmonary events that we evaluated within the first year after HSCT. Further evaluations in larger numbers of patients are needed to better clarify the role of ATG in the development of delayed pulmonary complications.

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n= 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

Non‐myeloablative autologous HSCT for relapsing remitting multiple sclerosis (RRMS) and new onset type 1 diabetes mellitus (TIDM)

Autologous non‐myeloablative hematopoietic stem cell transplantation (HSCT) is a method of delivering intense immune suppression. We, therefore, evaluated the safety and clinical outcome of autologous non‐myeloablative HSCT in 2 autoimmune diseases relapsing‐remitting multiple sclerosis (RRMS) failing interferon therapy and new onset Type 1 Diabetes mellitus. Peripheral blood hematopoietic stem cells (HSC) were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony stimulating factor (10 ug/kg/day). HSCT conditioning regimen was cyclophosphamide (200 mg/kg) and rabbit anti‐thymocyte globulin (either 6 mg/kg or 4.5 mg/kg).Eligible patients with RRMS had, despite interferon beta, 2 corticosteroid treated relapses within the prior 12 months, or 1 such relapse and gadolinium enhancing lesion(s) on magnetic resonance imaging (MRI) demonstrated on an occasion distinct from the relapse. All patients are surviving, 17 patients (81%) improved by at least 1.0 or more EDSS points, and five patients (24%) relapsed but achieved another remission after further immunosuppression. After a mean of 3 years, progression‐free survival is 100%, and relapse‐free survival is 76%. Significant improvement occurred in neurologic disability determined by extended disability status scale (EDSS), neurologic rating score (NRS), paced auditory serial addition test (PASAT), and 25 foot walk, as well as quality of life as measured by the short form‐36 (SF‐36). Non‐myeloablative autologous HSCT in RRMS appears capable of reversing neurologic deficits.Eligible patients for HSCT of T1DM were diagnosed in the previous 6 weeks by clinical findings and hyperglycemia and confirmed with positive antibodies against glutamic acid decarboxylase. 23 type 1 diabetic patients (aged between 13 and 31 years) were treated. During a 7‐to 58‐month follow‐up (mean 29.8) 20 patients without previous ketoacidosis and not receiving steroids during the preparative regimen became insulin‐free; 12 patients maintained this status for 14 to 52 months (mean 31) while 8 patients relapsed and resumed insulin use at low dose (0.1 to 0.3 IU/kg). In the continuous insulin‐independent group, HbA1c levels were always &lt;7.0%, continuous glucose monitoring was within normal levels and mean AUC of C‐peptide levels increased significantly from 225.0 ng/mL pre‐transplantation to 785.4 ng/mL at +24 months (P &lt;0.001) and to 728.1 ng/mL at +36 months (P = 0.03). In the transient insulin‐independent group mean AUC of C‐peptide levels also increased from 148.9 ng/ml before transplantation to 546.8 ng/mL at +36 months (P = 0.001) that was sustained at + 48 months In this group, two patients regained insulin independence after treatment with sitagliptin which was associated with increase in C‐peptide levels. HSCT induces insulin and drug free remission for up to 5 years post HSCT and appears to preserve or allow regeneration of islet cell mass with maximal C‐peptide levels reached 2–3 years after HSCT.

Optimizing stem cell transplantation in myelodysplastic syndromes: unresolved questions

Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Recent efforts to optimize the curative potential of transplant have focused on pretransplant therapy options, the use of predictive models to improve patient selection, and transplant modifications using reduced conditioning intensity. This review highlights strategies to optimize transplant for MDS and identifies unresolved questions. Debate surrounding pretransplant therapy and HCT conditioning intensity for MDS continues. The current literature fails to identify a superior pretransplant treatment regimen; however, for treated patients achieving complete remission, the data suggest that myeloablative conditioning may not be required for successful transplant outcomes. Patient selection for transplant is also critical, and predictive tools (WHO classification-based prognostic scoring system and hematopoietic cell transplantation comorbidity index) have helped identify patients who may derive the most transplant benefit. Prospective trials regarding optimal pretransplant therapy, utilization of patient selection tools, and conditioning intensity are warranted to improve transplant outcomes in MDS. Until those data are mature, current data suggest we initiate pretransplant therapy that minimizes toxicity and improves responses, try to optimize our patient selection using comorbidity (hematopoietic cell transplantation comorbidity index) and other predictive tools (WHO classification-based prognostic scoring system), and consider reduced intensity conditioning/nonmyeloablative conditioning in patients who have achieved a complete remission prior to transplant.

Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: Role of the Conditioning Regimen and the Type of Transplantation

There is endothelial activation and damage in hematopoietic stem cell transplantation (HSCT). The impact of the conditioning and type of HSCT on endothelial dysfunction in the early phases of HSCT has been evaluated. Plasma samples were obtained before and at different times after autologous and allogeneic HSCT with and without early complications. Changes in soluble markers of endothelial damage (VWF, ADAMTS-13, sVCAM-1, sICAM-1, and sTNFRI) were measured. There were changes in all markers evaluated that followed different patterns in auto and allo settings. For VWF and sTNRI, progressive increases from day Pre to day 14 and to day 21 were observed in the auto and the allo group, respectively. ADAMTS-13 activity correlated inversely with VWF levels. Levels of sVCAM-1 decreased until day 7, and raised significantly to day 14 and to day 21 in the auto and the allo HSCT, respectively. No significant changes were detected for sICAM-1. Our results confirm that there is endothelial damage at the early phases of HSCT, apparently induced by the consecutive effects of the conditioning, the proinflammatory agents used during transplantation, the translocation of endotoxins across the damaged gastrointestinal tract, and the engraftment. However, the comparative analysis between patients with and without complications suggests that none of these markers has diagnostic or prognostic value.