Biology of Blood and Marrow Transplantation - Articles in Press

Introduction to the Reports from the National Cancer Institute 1st International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation - Accepted Manuscript

2010-03-03

Thalidomide-Dexamethasone As Induction Therapy Prior To Autologous Stem-Cell Transplantation In Patients With Newly Diagnosed Multiple Myeloma And Renal Insufficiency - Accepted Manuscript

2010-03-02

Abstract: The aim of this study was to evaluate the efficacy and the toxicity of thalidomide-dexamethasone(Thal-Dex) as induction therapy prior to autologous peripheral blood stem-cell (PBSC) transplantation in newly diagnosed multiple myeloma (MM) patients with renal insufficiency.The study included 31 patients with baseline creatinine clearance values ≤50ml/min, 7 of whom were in chronic hemodyalisis. Patients received four months of Thal-Dex followed by PBSC collection and subsequent transplantation. After induction, a ≥ partial response (PR) was obtained in 23 patients (74%), including 8 (26%) who achieved a ≥ very good partial response (VGPR). Renal function improved more frequently in patients achieving ≥PR (82% vs. 37% in patients obtaining 4x106 CD34+ cells/kg were collected; a double or a single autologous transplantation were performed in 15 and 7 patients, respectively. Upon 32 months median follow-up, median event-free survival was 30 months, and median survival has not been reached. According to our data Thal-Dex is effective and safe in patients with newly diagnosed MM and renal insufficiency; given the relationship between recovery of renal function and response to induction treatment, more intensive Thal+bortezomib regimens could be explored in order to rescue a higher number of patients.

Predictors of Late Cardiovascular Complications in Survivors of Hematopoietic Cell Transplantation - Accepted Manuscript

2010-03-02

Abstract: Long-term survival after hematopoietic cell transplantation (HCT) is now an expected outcome. The growing population of survivors is at risk of developing treatment-related complications, including cardiovascular events (CVD). A nested case-control design was used to identify clinical and treatment-related risk factors for development of late (1+ years after HCT) CVD. Cases were identified from a cohort of one+ year survivors transplanted at City of Hope between 1977 and 2006. Controls (HCT survivors without CVD) were matched on age, year of HCT, type of HCT, and length of follow-up. Sixty-three patients with late CVD were identified; 44 (69.8%) with coronary artery events, and 19 (30.2%) with cerebrovascular events. Median age at HCT was 49.0 years; median age at late CVD was 54.0 years; 66.7% had undergone autologous HCT. Multivariate logistic regression analysis revealed multiple cardiovascular risk factors (≥2 of the following: obesity, dyslipidemia, hypertension, and diabetes) after HCT to be associated with a 5.2-fold increased risk of late CVD (p<0.01); pre-HCT chest radiation was associated with a 9.5-fold risk of coronary artery disease (p=0.03). Pre-HCT exposure to chest radiation and presence of comorbidities are primarily responsible for the risk associated with late CVD after HCT. These data form the basis for developing predictive models for identifying high-risk individuals for targeted surveillance and aggressive management of comorbidities.

Phase I/II Trial of GN-BVC, a Gemcitabine and Vinorelbine-Containing Conditioning Regimen for Autologous Hematopoietic Cell Transplantation in Recurrent and Refractory Hodgkin Lymphoma - Accepted Manuscript

2010-03-02

Abstract: Autologous hematopoietic cell transplantation with augmented BCNU-regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL), however BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m2, and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had one or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pre-transplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9% to 24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n=24), 1 (n=37), 2 (n=23), or 3 (n=8) risk factors, respectively. Regression analysis identified PET status pre-transplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

Activated Allogeneic NK Cells as Suppressors of Alloreactive Responses - Accepted Manuscript

2010-03-02

Abstract: Donor NK cells have been shown to be able to promote engraftment during allogeneic bone marrow transplantation. They could specifically suppress or delete host reactive cells, thereby facilitating engraftment of donor marrow. To further elucidate the mechanism, we showed that activated H2d ALAK cells (adherent lymphokine activated killer, IL-2 activated T cell depleted bone marrow and spleen cells) from BALB/c mice significantly suppressed the proliferation of H2b splenocytes from C57BL/6 mice in mixed lymphocyte responses (MLR) stimulated with irradiated H2d splenocytes from BALB/c mice (p<0.01). The ability for H2b splenocytes to kill H2d tumor targets was also significantly inhibited by activated H2d ALAK cells (p<0.01). The same number of H2b ALAK cells or H2d splenocytes did not show the same suppressive effect. These results suggested that activated H2d ALAK cells could specifically suppress the anti-H2d activity of the H2b splenocytes. Anti-TGFβ antibody blockade did not diminish this suppressive effect of ALAK cells, suggesting that this activity is not dependent on TGFβ secretion. ALAKs from gld (FasL mutant) mice suppressed the allo-responses as well as the wild type ALAK cells. The ALAKs from pfp (perforin knockout) mice did not completely block the inhibitory effect, which suggested that the suppressive effect of the allogeneic ALAK cells could be partially caused by perforin-mediated killing. We further demonstrated that donor ALAK cells could promote engraftment by suppressing host alloreactive responses in a nonmyeloablative allogeneic BMT model. These studies suggest that activated donor NK cells specifically suppress the alloreactive cells and provide a promising way to promote donor engraftment without involving systemic and nonspecific suppression of the immune system.

Decreased Infections in Recipients of Unrelated Donor Hematopoietic Cell Transplantation from Donors with an Activating KIR Genotype - Accepted Manuscript

2010-03-02

Abstract: Infectious complications following allogeneic hematopoietic cell transplantation (HCT) from unrelated donors (URD) result in significant morbidity. We hypothesized that recipients of an URD with an activating natural killer cell immunoglobulin-like receptor (KIR) (B/x) genotype would have decreased infectious complications due to enhanced NK cell function. We compared the infectious complications in 116 recipients of a graft from a donor with an A/A KIR (n = 44) genotype and a B/x KIR (n = 72) genotype. All recipients participated in the prospective NMDP infection project collecting infection data from conditioning until six months post-transplant. The cohort with a B/x donor had fewer initial bacterial infections by day 180 (A/A: 86% [95% CI, 75 – 95]; B/x: 68% [95% CI, 57 – 78]; p=0.02). There was no difference in the incidence of viral or fungal infections. When accounting for multiple infections, fewer bacterial infections were seen in the B/x cohort (A/A: 3.55/patient; B/x: 2.63/patient; p = 0.09). During the study period, only 19 patients had no infections; of these, 15 had received cells from a B/x KIR donor. The role of donor KIR genotype on infection complications is intriguing and warrants further investigation.

Erratum - Uncorrected Proof

2010-02-26

In “Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease” (Walters et al., Biol Blood Marrow Transplant 2009:16:263–272) the following author was omitted: Ann Haight, MD, Emory University, Atlanta, GA.

Accelerated bone mineral density loss occurs with similar incidence and severity, but with different risk factors, after autologous vs. allogeneic hematopoietic cell transplantation - Accepted Manuscript

2010-02-25

Abstract: Bone mineral density (BMD) loss occurs commonly in patients after allogeneic hematopoietic cell transplantation (HCT) primarily due to steroid use, but little is known about BMD change post-autologous HCT. In a prospective study of 206 consecutive first HCT patients, we measured acute BMD change at the lumbar spine and dual femur between baseline and day +100, and evaluated risk factors for bone loss. Accelerated BMD loss in this 4-month period occurred after both autologous and allogeneic HCT with similar severity (median, 0.03 g/cm2 vs 0.03 g/cm2 at the spine; 0.03 g/cm2 vs 0.05 g/cm2 at the femur, respectively). This is equivalent to 7-17 years’ worth of bone loss by aging. Risk factors for BMD loss were different between autologous and allogeneic HCT patients: lymphoma was associated with greater bone loss after autologous HCT than myeloma; while higher steroid dose was the most significant risk factor after allogeneic HCT. Multivariable risk models explained 11-30% of the variation in HCT-related BMD change. Surprisingly, BMD loss post-autologous HCT occurred with similar incidence and severity to allogeneic HCT, even in the absence of steroid use. Evaluation of clinical strategies to prevent and reverse HCT -related BMD loss is necessary in both autologous and allogeneic HCT patients.

Natural killer cell enriched donor lymphocyte infusions from a 3-6/6 hla matched family member following non-myeloablative allogeneic stem cell transplantation - Accepted Manuscript

2010-02-25

Abstract: Purpose: Infusing Natural Killer (NK) cells following transplantation may allow less infections and relapse with little risk of acute graft versus host disease (aGVHD). We delivered 51 total NK cell enriched donor lymphocyte infusions (DLIs) to 30 patients following a 3-6/6 HLA matched T cell depleted nonmyeloablative allogeneic transplant. The primary endpoint of this study was feasibility and safety.Methods: Eight weeks following transplantation, donor NK cell enriched DLIs were processed using a CD56+ selecting column (@Miltenyi) with up to 3 fresh infusions allowed. Toxicity, relapse and survival were monitored. T cell phenotype, NK cell functional recovery, and KIR typing were assessed for association with outcomes.Results: Fourteen matched and sixteen mismatched transplanted patients received a total of 51 NK cell enriched DLIs. Selection resulted in 96% (standard deviation (SD) 8%) purity and 83% (SD 21%) yield in the matched setting and 97% (SD 3%) purity and 77% (SD 24%) yield in the mismatched setting. The median number of CD3- CD56+ NK cells infused was 10.6 (SD 7.91) x 10e6 cells/kg and 9.21 (SD 5.6) x 10e6 cells/kg respectively. The median number of contaminating CD3+CD56- T cells infused was.53 (1.1) x 10e6 and.27 (.78) x 10e6 in the matched and mismatched setting respectively. Only 1 patient each in the matched (n=14) or mismatched (n=16) setting experienced severe aGVHD with little other toxicity attributable to the infusions. Long term responders with multiple NK cell enriched infusions and improved T cell phenotypic recovery had improved duration of responses (p=.0045) and overall survival (p=.0058).Conclusions: A one step, high yield process is feasible and results in high doses of NK cells infused with little toxicity. NK cell enriched DLIs result in improved immune recovery and outcomes for some. Future studies must assess whether the improved outcomes are the direct result of the high doses and improved NK cell function or other aspects of immune recovery.

Prediction Of Veno-Occlusive Disease Using Biomarkers Of Endothelial Injury - Accepted Manuscript

2010-02-24

Abstract: Predicting the development of veno-occlusive disease of the liver (VOD) remains challenging. We hypothesized that biomarkers of endothelial injury in myeloablative allogeneic transplant recipients could predict VOD occurrence. We evaluated 4 biomarkers (von Willebrand Factor (vWF), thrombomodulin, E-selectin and soluble intercellular adhesion molecule-1 (sICAM-1) weekly in the peri-transplant period in an attempt to predict VOD. Among patients who received sirolimus, vWF, thrombomodulin and sICAM-1 levels were significantly elevated in VOD patients in comparison with patients without VOD on day -1 (p≤0.035), day+7 (p≤0.0001) and day+14 (p≤0.004). E-selectin was predictive on day+7 (p=0.007). vWF ≥1400 IU/ml and TM ≥ 100 ng/ml levels on day +7 were both 100% sensitive and 100% specific in predicting VOD. These biomarkers were informative when adjusted for other risk factors for VOD in regression analysis. Among non-sirolimus patients, biomarkers of endothelial injury were not informative. We conclude that vWF, thrombomodulin and sICAM-1 elevations before and early after transplantation may be useful in predicting VOD in patients receiving sirolimus.

Favorable Outcome in Patients with Acute Myeloid Leukemia with NPM1 Mutation Autografted after Conditioning with High-Dose Continuous Infusion Idarubicin and Busulphan - Uncorrected Proof

2010-02-22

Abstract: Mutations of the nucleophosmin gene (NPM1), in the absence of concurrent FLT3-internal tandem duplication (FLT3-ITD) have impressive prognostic value in patients with acute myeloid leukemia (AML), carrying normal karyotype (NK). In this study we describe treatment results from a series of 19 patients with NPM+/FLT3− autografted in first complete remission (CR) after conditioning with a regimen, named BuI, based on high-dose continuous infusion idarubicin and Busulphan. Ninety-nine consecutive patients (median age of 54 years) with NK AML autografted in first CR were analyzed. Nineteen out of 99 patients (19%) had NPM1 mutation in the absence of FLT3 mutations. The control group, accounting for 80 patients, included 16 cases (15%) with both mutations, 10 (12%) with FLT3/ITD mutation and no NPM mutation, and 54 (68%) in whom neither NPM1 nor FLT3 mutations were detectable. The median overall survival (OS) for the whole patient population was 34 months, the median disease-free survival (DFS) was 22 months. Median OS and DFS were significantly longer for patients with isolated NPM1 mutation as opposed to controls (OS: not reached versus 25 months, P = .02; DFS: not reached versus 16 months, P = .007, respectively). Of interest, patients with isolated NPM1 mutation had a better outcome in terms of either OS or DFS compared to the group of 16 NMP1+/FLT3+ patients. In conclusion, our study suggest that BuI regimen results in favorable clinical outcome in patients with isolated NPM1 mutation, and could be investigated in a randomized study versus other regimes or repeated courses of high dose cytosine-arabinoside.

An Approach to Predicting HSCT Outcome Using HLA-Mismatch Information Mapped on Protein Structure Data - Uncorrected Proof

2010-02-22

We wish to comment on 3 aspects of the recently published article by Dudkiewicz et al : (1) , which erroneously summarizes current practice in donor selection; (2) our concerns about the analyses attempting to validate the recommendations in ; and (3) the use of contact energy calculations to predict immunogenicity of specific HLA mismatches.

Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure - Uncorrected Proof

2010-02-22

Abstract: Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We describe the results of 122 patients reported to the National Marrow Donor Program between 1990 and 2005, who received a second unrelated donor HCT after failing to achieve an absolute neutrophil count of ≥500/μL without recurrent disease. Patients were transplanted for leukemia (n = 83), myelodysplastic disorders (n = 16), severe aplastic anemia (n = 20), and other diseases (n = 3). The median age was 29 years. Twenty-four patients received second grafts from a different unrelated donor. Among 98 patients who received a second graft from the same donor, 28 received products that were previously collected and cryopreserved for the first transplantation. One-year overall survival (OS) after second transplant was 11%, with 10 patients alive at last follow-up. We observed no differences between patients who received grafts from the same or different donors, or in those who received fresh or cryopreserved product. The outcomes after a second allogeneic HCT for primary graft failure are dismal. Identifying risk factors for primary graft failure can decrease the incidence of this complication. Further studies are needed to test whether early recognition and hastened procurement of alternative grafts can improve transplant outcomes for primary graft failure.

Donor Derived Second Hematologic Malignancies after Cord Blood Transplantation - Accepted Manuscript

2010-02-22

Abstract: Double umbilical cord blood transplantation with a reduced intensity regimen is an effective strategy for adult patients without matched donors. However, the risk of second cancers is not yet established. Ninety-eight adults with hematologic malignancies received a double umbilical cord blood transplant. Seventy patients received the reduced intensity regimen of fludarabine 30 mg/m2/day x 6 days, melphalan 100 mg/m2/day x 1 day, and rabbit antithymocyte globulin 1.5 mg/kg/day x 4 days, and 28 patients received an ablative total body radiation containing conditioning regimen. Sixty-three patients received sirolimus-based graft versus host disease prophylaxis and 35 patients received non-sirolimus based graft versus host disease prophylaxis. Median age was 48 (range 19-67) years. Eighteen patients developed a second malignancy at a median of 134 days after transplant. Sixteen patients had lymphoma and two patients had myelodysplasia/myeloproliferative disorder. Sixteen of these second cancers (both MDS/MPD and fourteen of the lymphomas) were donor derived; the origin of the others was not determined. GVHD prophylaxis, HLA matching, primary disease, age, total nucleated cell dose, and CD34+ cell dose were not associated with a higher rate of second malignancy. Second myeloid malignancies of donor origin occur after double umbilical cord blood transplantation, suggesting that a search for donor origin should be performed in all patients with suspected relapse.

Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed Multiple Myeloma - Accepted Manuscript

2010-02-22

Abstract: Purpose: Despite recent advances, multiple myeloma remains incurable and most patients eventually develop progressive disease. Allogeneic hematopoietic stem cell transplantation (allo HCT) offers a potentially curative option in 10-20% of patients with relapsed or refractory disease. We evaluated the outcome of patients undergoing allo HCT with reduced-intensity conditioning (RIC) for relapsed and/or refractory myeloma at our institution.Methods: Fifty-one patients with heavily pretreated, relapsed myeloma, who received RIC allo HCT between 1996 and 2006, were included in this analysis.Results: Median time from diagnosis to allo HCT was 34 months. Median follow-up in surviving patients was 27 months (3-98). Cumulative transplant-related mortality (TRM) at 1 year was 25%. Progression-free survival (PFS) and overall survival (OS) at 2 years were 19% and 32%, respectively. The incidence of grade II-IV acute or chronic graft-vs-host disease (GVHD) was 27% and 47%, respectively. At the time of this analysis, 12 patients (24%) were alive 7 of whom (14%) were in remission for up to 6 years after allo SCT. A lower β2 microglobulin (<3.3) and a prior autotransplant predicted a lower NRM, longer PFS and OS.Conclusion: Allo HCT with RIC regimens is associated with acceptable toxicity and durable remission and survival in relapsed or refractory myeloma. Use of RIC allo HCT earlier in the course of the disease may offer greater benefit.

Protective Immunity Transferred by Infusion of Cytomegalovirus-Specific CD8+ T Cells within Donor Grafts: Its Associations with Cytomegalovirus Reactivation Following Unmanipulated Allogeneic Hematopoietic Stem Cell Transplantation - Uncorrected Proof

Xiao-Hua Luo, Xiao-Jun Huang, Kai-Yan Liu, Lan-Ping Xu, Dai-Hong Liu — 2010-02-17

Abstract: Human cytomegalovirus (CMV)-specific cytotoxic T lymphocyte (CTL) immune response must be reconstituted for long-term protection against CMV relapse and disease in hematopoietic stem cell transplantation (HSCT) recipients. We phenotypically quantitated absolute numbers of CMV-pp65 peptide-specific CTLs (CTLCMV) in 50 related donor unmanipulated allografts infused into HLA-matched or -mismatched recipients and examined the incidence of CMV reactivation. High CTLCMV with terminally differentiated effector CD45RO-CD62L- cell (TEMRA) phenotype in the allografts were associated with reduced risk of CMV reactivation, in the presence of sufficient CD45RO+CD62L- cell (TEM) infusion (≥0.208 × 106/kg). Early after transplantation, there was significant expansion of CTLCMV with the central memory CD45RO+CD62L+ cell (TCM) phenotype when CMV was reactivated. The frequencies of CTLCMV TNaive (CD45RO-CD62L+), TCM, and TEM at day 90 posttransplantation and of CTLCMV TEMRA at day 60 posttransplantation were greater in recipients with higher infusions of CTLCMV TEMRA, suggesting protective immunity transferred by infusion of CTLCMV within allografts. Moreover, the majority of the CTLCMV identified in the recipients early after HSCT was of donor origin. Our findings support that measuring levels of CTLCMV and its subsets in the donor grafts and manipulating these cells early after transplantation may help control CMV reactivation, which is closely correlated with immune reconstitution and differentiation of CTLCMV subsets.

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

2010-02-17

Abstract: 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.

Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease and Multiorgan Failure after Stem Cell Transplantation: A Multicenter, Randomized, Dose-Finding Trial - Uncorrected Proof

2010-02-17

Abstract: Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for ≥14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment also was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity, or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

Preparing for Growth: Current Capacity and Challenges in Hematopoietic Stem Cell Transplantation Programs - Uncorrected Proof

Jeffrey R. Schriber, Claudio Anasetti, Helen E. Heslop, Alan K. Leahigh — 2010-02-17

Abstract: During the past decade, the demand for hematopoietic stem cell transplantation has grown dramatically, and there are expectations that this will continue or even accelerate over the next decade. This prompts a variety of questions about the ability of the health care system to accommodate the increased demands on transplantation centers; for example, what is the current patient capacity of transplantation programs, and how much elasticity do they have to accept a larger volume of patients? An informal survey of a sample of medical directors of transplantation programs found that existing facilities might be able to increase their patient volume by about 7%. Expanding much beyond that limit will require an infusion of resources to enlarge current programs and/or establish new programs.

Chronic Kidney Disease, Thrombotic Microangiopathy, and Hypertension Following T Cell-Depleted Hematopoietic Stem Cell Transplantation - Uncorrected Proof

2010-02-15

Abstract: Chronic kidney disease (CKD) is now an accepted long-term complication of allogeneic hematopoietic stem cell transplantation. Calcineurin inhibitors (CNI), which are used for prophylaxis and treatment of graft-versus-host disease (GVHD), have been associated with the development of nephrotoxicity. Hypertension (HTN) and thrombotic microangiopathy (TMA) are 2 comorbidities linked to CKD. T cell depletion (TCD) of stem cell grafts can obviate the need for the use of CNI. We conducted a retrospective analysis of 100 patients who underwent TCD transplantation: 30 in group A were conditioned without total-body radiation (TBI) and 70 in group B received a TBI containing regimen. None of the patients received CNI. The median age was 55.5 and 45 years for groups A and BM, respectively. Eleven patients developed TMA, all in group B. The 2-year cumulative incidence of sustained CKD was 29.2% and 48.8% in group A and group B, respectively, with a mean follow-up of at least 21 months. CKD free survival was better in the non-TBI group (= .046). Multivariable survival analysis revealed that exposure to TBI, older age, and TMA were risk factors for CKD. The incidence of new onset or worsening HTN was 6.7% and 25.7% (P = .03) in group A and B, respectively. The use of TBI (P = .0182) and diagnosis of TMA (P = .0006) predisposed patients to the development of HTN using univariable logistic regression models. Thus, despite the absence of CNI, a proportion of these older patients in both groups developed CKD and HTN.

NCI First International Workshop on The Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Biology Underlying Recurrence of Malignant Disease following Allogeneic HSCT: Graft-versus-Tumor/Leukemia Reaction - Uncorrected Proof

2010-02-11

Abstract: ▪▪▪

Oral Symptom Intensity, Health-Related Quality of Life, and Correlative Salivary Cytokines in Adult Survivors of Hematopoietic Stem Cell Transplantation with Oral Chronic Graft-versus-Host Disease - Uncorrected Proof

2010-02-08

Abstract: Oral chronic graft-versus-host disease (cGVHD) is a frequent, clinically significant sequela of allogeneic hematopoietic stem cell transplantation (HSCT). This study was designed to elucidate relationships among clinical characteristics of oral cGVHD and related oral pain and oral dryness, salivary proinflammatory cytokine interleukin (IL)-6 and IL-1α concentrations, and health-related quality of life (HRQL). An understanding of the characteristics and correlates of oral cGVHD manifestations and related symptoms, such as oral dryness, is fundamental to the development of therapeutic interventions. Oral cGVHD severity was assessed with the Oral Mucositis Rating Scale (OMRS). Oral pain and perceived intensity of oral dryness were self-reported via a visual analogue scale and a numeric rating scale, respectively. HRQL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G). Salivary IL-1α and IL-6 concentrations were measured by enzyme-linked immunosorbent assay. All 42 adult subjects (59% males) had clinician-assessed oral cGVHD by the OMRS scale (mean score, 18.38 ± 12.99; range, 2-46). Oral dryness (in 43% of subjects; mean OMRS score, 2.56 ± 3.45; range, 0-10) was more prevalent than oral pain (8%; mean score, 0.13 ± 0.47). Salivary IL-6 was associated with oral cGVHD severity (r = 0.49; P < .01), oral ulceration (r = 0.38; P = .04), and erythema (r = 063; P < .01). FACT-G total score and physical and emotional well-being subscale scores were meaningfully lower than US population normative values. Participants with more severe oral cGVHD manifestations had significantly inferior social/family well being (r = -0.49; P < .01). Oral dryness was associated with higher salivary IL-1α (r = 0.41; P = .04) and, controlling for cGVHD severity, with lower HRQL (r = -0.41; P = .03). Subjects with moderate to severe oral dryness tended to report the poorest overall HRQL. This study provides preliminary evidence of the relationship between oral dryness and HRQL, the contribution of oral cGVHD to inferior HRQL, and the association between IL-6 and oral cGVHD severity, ulceration, and erythema. The high prevalence of oral dryness and its relationship to HRQL in a sample of subjects with oral cGVHD underscores the importance of improving our evaluation and management of this symptom in long-term survivors of allogeneic HSCT. The positive associations between IL-6 and oral sGVHD severity and erythema, as well as the positive trend with oral ulceration, warrant further exploration of this cytokine as a potential biomarker of active oral cGVHD.

Long-Term Follow-Up of an Intensified Myeloablative Conditioning Regimen with In Vivo T Cell Depletion Followed by Allografting in Patients with Advanced Multiple Myeloma - Uncorrected Proof

2010-02-08

Abstract: We report long-term results after a median follow-up of 105 months in 18 patients with multiple myeloma who received an intensified myeloablative conditioning regimen regimen consisting of modified total body irradiation, busulfan, cyclophosphamide, and antithymocyte globulin, followed by allogeneic stem cell transplantation (SCT). Grade II-IV acute graft-versus-host disease occurred in 7 patients (44%), and treatment-related mortality was 17%. Complete remission (CR) with negative immunofixation after allogeneic SCT occurred in 53% of the patients. For all patients, the estimated overall survival at 12 years was 50% (95% confidence interval [CI], 26%-74%), and the estimated progression-free survival (PFS) was 35% (95% CI, 23%-57%). Those patients who achieved CR after SCT had a 12-year estimated PFS of 60%, whereas none of the patients without CR remained progression-free. Our data indicate that an intensified myeloablative conditioning regimen followed by allogeneic SCT can produce long-term survival and freedom from disease in patients with multiple myeloma who achieve CR.

Response to Letter from Demetrios S. Theodoropoulos, MD, DSc - Uncorrected Proof

James L. Gajewski, Michael C. Lill, Mary M. Horowitz, Richard T. Maziarz — 2010-02-08

We appreciate Dr. Theodoropoulos' letter and comments . Dr. Theodoropoulos points out that the rapid changes in medicine today in both personalized molecular medicine and the emerging field of regeneration medicine is creating a new landscape that may alter our projections for the need for an expanded hematopoietic stem cell transplantation (HSCT) workforce over the next decade. He is correct that these numbers could ultimately be curbed somewhat from our projections that were made based on the changing demographics of the aging population of this country, the expanded indications, and as have been documented with the recent publication by the Healthcare Cost and Utilization Project, which demonstrated that bone marrow transplant (BMT) was associated with the greatest percentage change and total hospital stay during the years 2004 to 2007 . However, based on our current appreciation of personalized molecular and regeneration medicine, we can at least be assured that reduction in transplant procedures will not occur in the near future.

Natural Killer Cell Killing of Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia Blasts by Killer Cell Immunoglobulin-Like Receptor–Negative Natural Killer Cells after NKG2A and LIR-1 Blockade - Uncorrected Proof

2010-02-08

Abstract: Although natural killer (NK) cell alloreactivity has been dominated by studies of killer cell immunoglobulin-like receptors (KIRs), we hypothesized that NKG2A and LIR-1, present on 53% ± 13% and 36% ± 18% of normal NK cells, respectively, play roles in the NK cell killing of primary leukemia targets. KIR- cells, which compose nearly half of the circulating NK cell population, exhibit tolerance to primary leukemia targets, suggesting signaling through other inhibitory receptors. Both acute myelogenous leukemia and acute lymphoblastic leukemia targets were rendered susceptible to lysis by fresh resting KIR- NK cells when inhibitory receptor–major histocompatibility class I interactions were blocked by pan-HLA antibodies, demonstrating that these cells are functionally competent. Blockade of a single inhibitory receptor resulted in slightly increased killing, whereas combined LIR-1 and NKG2A blockade consistently resulted in increased NK cell cytotoxicity. Dual blockade of NKG2A and LIR-1 led to significant killing of targets by resting KIR- NK cells, demonstrating that this population is not hyporesponsive. Together these results suggest that alloreactivity of a significant fraction of KIR- NK cells is determined by NKG2A and LIR-1. Thus strategies to interrupt NKG2A and LIR-1 in combination with anti-KIR blockade hold promise for exploiting NK cell therapy in acute leukemias.

Comparison of Unmobilized and Mobilized Graft Characteristics and the Implications of Cell Subsets on Autologous and Allogeneic Transplantation Outcomes - Uncorrected Proof

Stefan Fruehauf, Guido Tricot — 2010-02-08

Abstract: Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are considered the standard of care for many malignancies, including lymphoma, myeloma, and some leukemias. In many cases, mobilized peripheral blood has become the preferred source of hematopoietic stem cells. The efficacy of different mobilization regimens and transplantation outcomes based on cell doses has been well studied; however, the characteristics of the stem cell graft may be of equal importance with respect to patient outcomes following autologous or allogeneic HSCT. This review summarizes available preclinical and clinical data for bone marrow and mobilized peripheral blood HSCT characteristics, defined as the cell types found in the graft as well as their gene expression profiles. It also explores how graft characteristics can affect bone marrow homing, engraftment, immune reconstitution, and other posttransplantation outcomes in both the allogeneic and autologous HSCT settings.

Unrelated Transplantation for Poor-Prognosis Adult Acute Lymphoblastic Leukemia: Long-Term Outcome Analysis and Study of the Impact of Hematopoietic Graft Source - Uncorrected Proof

2010-02-08

Abstract: Adults with high-risk acute lymphoblastic leukemia (HR-ALL) have a poor outcome with standard chemotherapy and usually undergo unrelated stem cell transplantation (SCT) if a matched sibling donor is not available. We analyzed the outcome of adult patients with unrelated SCT for HR-ALL and studied the possible effect of the hematopoietic stem cell source of the transplant. A total of 149 adult patients (median age, 29 years, range, 15-59 years) with HR-ALL underwent unrelated SCT in 13 Spanish institutions between 2000 and 2007. Patients in first complete remission (CR1) at transplantation had at least one adverse prognostic factor (advanced age, adverse cytogenetics, hyperleukocytosis, or slow response to induction therapy). ALL was in CR1 in 81 patients (54%), in second CR (CR2) in 37 patients (25%), in third CR (CR3) in 11 patients (7%), and with overt disease in 20 patients (13%). The hematopoietic source was unbilcal cord blood (UCB) in 62 patients and an unrelated donor (UD) in 87 patients. The patients undergoing UCB-SCT and UD-SCT were comparable in terms of the main clinical and biological features of ALL, except for a higher frequency of patients with more overt disease in the UCB-SCT group. There was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) at 5 years between the 2 groups. Transplantation-related mortality (TRM) was significantly lower in the UCB-SCT group (P = .021). The probability of relapse at 1 year was 17% (95% confidence interval [CI], 7%-27%) for the UD-SCT group and 27% (95% CI, 14%-40%) for the UCB-SCT group (P = .088). Only disease status at transplantation (CR1/CR2/more advanced disease: 41% [95% CI, 18%-64%] vs 51% [95% CI, 17%-85%] vs 66% [95% CI, 46%-86%]; P = .001) and the absence of chronic GVHD (74% [95% CI, 46%-100%] vs 33% [95% CI, 17%-49%]; P = .034) were significant factors for relapse. All unrelated transplantation modalities were associated with high TRM for adult HR-ALL patients without a sibling donor. UCB-SCT and UD-SCT were found to be equivalent options. Disease status at transplantation and chronic GVHD were the main factors influencing relapse in both transplantation modalities.

Prognostic Factor and Quality of Life Analysis in 160 Patients Age ≥60 Years with Hematologic Neoplasias Treated with Allogeneic Hematopoietic Cell Transplantation - Uncorrected Proof

2010-02-08

Abstract: Toxicity-reduced conditioning is a curative treatment option for medically compromised or elderly patients ineligible for myeloablative hematopoietic cell transplantation (HCT). The aim of this study was to detect prognostic factors for overall survival (OS) and to evaluate quality of life (QOL) in a large homogeneous cohort of 160 consecutive patients age ≥60 years treated with allogeneic HCT. We evaluated age, sex, performance status, comorbidities, pulmonary function, lactic dehydrogenase concentration, type of donor, disease status, CD34+ cells transplanted, cytomegalovirus status, time from diagnosis to HCT, and the development of acute and chronic graft-versus-host disease (GVHD). All patients who survived for ≥6 months (n = 79) were asked to complete a QOL survey. All patients (median age, 64.7 years; range, 60.1-76 years) received pretransplantation conditioning with fludarabine, BCNU, and melphalan. With a median follow-up of 35 months, the 1-year OS was 62.4% and 3-year OS was 47.4%. Multivariate analysis revealed compromised performance status as the most significant negative prognostic parameter for OS (P < .003), whereas male donor (P = .008) and chronic GVHD (P = .024) were associated with better OS. The 89% of survivors who returned the QOL questionnaire rated their global QOL as good-to-excellent despite impaired functional capabilities and such symptoms as fatigue, dyspnea, and loss of appetite. The main prognostic factor was performance status, not age. Our data suggest that toxicity-reduced conditioning offers a chance for enhanced OS with an adequate QOL.

Dendritic Cell Count in the Graft Predicts Relapse in Patients with Hematologic Malignancies Undergoing an HLA-Matched Related Allogeneic Peripheral Blood Stem Cell Transplant - Uncorrected Proof

2010-02-05

Abstract: We investigated the impact of the number of infused and reconstituted immunocompetent cells including dendritic cells (DC) on clinical outcome of patients with hematologic malignancies under going an allogeneic PBSCT. Sixty-nine consecutive patients with hematologic malignancies were included in the analysis. The median age of the cohort was 32 years (range: 2-62) and there were 39 (57%) males. Twenty-one (30%) patients relapsed with a cumulative incidence of 44 ± 14% at a median follow up of 28 months. On a multivariate analysis, a high plasmacytoid dendritic cell (PC) content in the graft was associated with higher risk of relapse. The patients were further categorized based on the median PC counts in the graft as high (≥2.3 × 106/kg) and low (<2.3 × 106/kg) groups. The baseline characteristics of these 2 groups were comparable. The group that had a high PC content in the graft had significantly higher risk of relapse and lower overall survival (OS) and event-free survival (EFS). Our data suggests that PC content in the graft predicts clinical outcomes such as relapse and survival in patients with hematologic malignancies under going an allogeneic HLA matched related PBSCT. There is potential for pretransplant manipulation of this cellular subset in the graft.

Response to Krejci and Mayer - Corrected Proof

Paul J. Martin, George B. McDonald — 2010-02-05

We thank Drs. Krejci and Mayer for highlighting the potential value of considering serum aminotransferase enzyme (AST, ALT) concentrations in assessing outcomes of treatment for acute graft-versus-host disease (GVHD) of the liver. Liver GVHD has 3 components . The first involves a cytokine-mediated effect on hepatocyte transport of conjugated bilirubins into bile, primarily in patients with more severe gut GVHD. These cases present as isolated hyperbilirubinemia (cholestasis) with no histologic findings . The second involves T cell-mediated apoptosis of small bile duct epithelial cells , with hyperbilirubinemia as the principal clinical biomarker. The third involves T cell-mediated hepatocyte necrosis and lobular inflammation, also described as hepatitic GVHD, often occurring together with bile duct injury and hyperbilirubinemia.

Evaluation of Response in Hepatitic Variant of Acute Liver Graft-versus-Host Disease - Uncorrected Proof

Marta Krejci, Jiri Mayer — 2010-02-05

Acute graft-versus-host disease (aGVHD) causes serious morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recently, Martin et al. defined important endpoints for clinical trials testing treatment of aGVHD. Criteria for very good partial response (VGPR) of aGVHD were described for skin, liver, and gut. Correct and objective evaluation of treatment response is very important, and the new category of VGPR can be useful for several reasons discussed by Martin et al. in their article. Persisting low-level hyperbilirubinemia is allowed, which might be related to antecedent regimen-related hepatotoxicity, or administration of hepatotoxic agents, or other factors.

Targeted Agents for CML: Will That Be the End of Allogeneic Bone Marrow Transplantation for That Disease? - Uncorrected Proof

2010-02-05

Abstract: Although the drug imatinib has been accepted as the treatment of choice for chromic myeloid leukemia (CML) in chronic phase (CP) throughout the Western world, allogeneic stem-cell transplantation (allo-SCT) continues to remain a widely practiced first-line treatment in countries with limited healthcare budgets. The rationale is not scientific, but largely economically based. We analyzed a cohort of 46 CML patients who participated in a graft-versus-host disease (GVHD) prophylaxis clinical trial and underwent related HLA-matched allogeneic peripheral blood stem cell transplantation. The median time of follow-up in surviving patients was 43 months (range: 4-89 months). Risk stratification of the population was done by European Blood and Marrod Transplant (EBMT) criteria. The estimated probabilities of overall survival (OS) and leukemia-free survival (LFS) at 3 years in low EBMT risk score (0-2) patients were both 91%, respectively. We conclude that in countries with restricted access to imatinib, allo-SCT should be considered early on as front-line therapy. Continued research support for bone and marrow transplantation (BMT) will be needed to make a global impact on this disease.

Secondary Lymphoid Organs Contribute to, but Are Not Required for the Induction of Graft-versus-Host Responses following Allogeneic Bone Marrow Transplantation: A shifting Paradigm for T Cell Allo-activation - Uncorrected Proof

2010-02-01

Abstract: Graft-versus-host disease (GVHD) remains the major complication of allogeneic bone marrow transplantation (allo-BMT). GVHD fundamentally depends upon the activation of donor T cells by host antigen-presenting cells (APCs), but the precise location of these interactions remains uncertain. We examined the role of secondary lymphoid organs (SLO) in the induction of GVHD by using homozygous aly/aly mice that are deficient in lymph nodes (LNs) and Peyer's patches (PPs). Lethally irradiated, splenectomized, aly/aly (LN/PP/Sp−/−) mice and sham-splenectomized, aly/+ (LN/PP/Sp+/+) mice received BMT from either syngeneic (aly/aly) or allogeneic, major histocompatibility complex (MHC) disparate donors. Surprisingly, although LN/PP/Sp−/− allo-BMT recipients experience a survival advantage, they developed significant systemic and target organ GVHD that is comparable to LN/PP/Sp+/+ controls. Early after allo-BMT, the activation and proliferation of donor T cells was significantly greater in the BM cavity of LN/PP/Sp−/− mice compared to LN/PP/SP+/+ controls. Donor T cells in LN/PP/Sp−/− mice demonstrated cytolytic activity in vitro, but GVL activity could be overcome by increasing the tumor burden. These data suggest that SLO contribute to, but are not required for, allogeneic T cell responses, and suggest that the bone marrow may represent an alternative, albeit less efficient site for T cell activation following allo-BMT.

Identification of Stem Cell Transcriptional Programs Normally Expressed in Embryonic and Neural Stem Cells in Alloreactive CD8+ T Cells Mediating Graft-versus-Host Disease - Uncorrected Proof

2010-01-29

Abstract: A hallmark of graft-versus-host-disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is the cytopathic injury of host tissues mediated by persistent alloreactive effector T cells (TE). However, the mechanisms that regulate the persistence of alloreactive TE during GVHD remain largely unknown. Using mouse GVHD models, we demonstrate that alloreactive CD8+ TE rapidly diminished in vivo when adoptively transferred into irradiated secondary congenic recipient mice. In contrast, although alloreactive CD8+ TE underwent massive apoptosis upon chronic exposure to alloantigens, they proliferated in vivo in secondary allogeneic recipients, persisted, and caused severe GVHD. Thus, the continuous proliferation of alloreactive CD8+ TE, which is mediated by alloantigenic stimuli rather than homeostatic factors, is critical to maintaining their persistence. Gene expression profile analysis revealed that although alloreactive CD8+ TE increased the expression of genes associated with cell death, they activated a group of stem cell genes normally expressed in embryonic and neural stem cells. Most of these stem cell genes are associated with cell cycle regulation, DNA replication, chromatin modification, and transcription. One of these genes, Ezh2, which encodes a chromatin modifying enzyme, was abundantly expressed in CD8+ TE. Silencing Ezh2 significantly reduced the proliferation of alloantigen-activated CD8+ T cells. Thus, these findings identify that a group of stem cell genes could play important roles in sustaining terminally differentiated alloreactive CD8+ TE and may be therapeutic targets for controlling GVHD.

The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Follicular Lymphoma: An Evidence-Based Review - Uncorrected Proof

2010-01-28

Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of follicular non-Hodgkin lymphoma in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations reached unanimously by a panel of follicular lymphoma experts are: (1) autologous SCT is recommended as salvage therapy based on prerituximab data, with a significant improvement in overall survival (OS) and progression-free (PFS) survival; (2) autologous SCT is not recommended as first-line treatment for most patients because of no significant improvement in OS; (3) autologous SCT is recommended for transformed follicular lymphoma patients; (4) reduced intensity conditioning before allogeneic SCT appears to be an acceptable alternative to myeloablative regimens; (5) an HLA-matched unrelated donor appears to be as effective an HLA-matched related donor for reduced intensity conditioning allogeneic SCT. There are insufficient data to make a recommendation on the use of autologous SCT after rituximab-based salvage therapy. Eleven areas of needed research in the treatment of follicular lymphoma with SCT were identified and are presented in the review.

Cotransplantation of Mesenchymal Stem Cells Might Prevent Death from Graft-versus-Host Disease (GVHD) without Abrogating Graft-versus-Tumor Effects after HLA-Mismatched Allogeneic Transplantation following Nonmyeloablative Conditioning - Corrected Proof

2010-01-27

Abstract: Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD) after myeloablative allogeneic HCT. This prompted us to investigate in a pilot study whether MSC infusion before HCT could allow nonmyeloablative (NMA) HCT (a transplant strategy based nearly exclusively on graft-versus-tumor effects for tumor eradication) from HLA-mismatched donors to be performed safely. Twenty patients with hematologic malignancies were given MSCs from third party unrelated donors 30-120 minutes before peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors, after conditioning with 2 Gy total body irradiation (TBI) and fludarabine. The primary endpoint was safety, defined as a 100-day incidence of nonrelapse mortality (NRM) <35%. One patient had primary graft rejection, whereas the remaining 19 patients had sustained engraftment. The 100-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was 35%, whereas 65% of the patients experienced moderate/severe chronic GVHD (cGVHD). One-year NRM (10%), relapse (30%), overall survival (OS) (80%) and progression-free survival (PFS) (60%), and 1-year incidence of death from GVHD or infection with GVHD (10%) were encouraging. These figures compare favorably with those observed in a historic group of 16 patients given HLA-mismatched PBSCs (but no MSCs) after NMA conditioning, which had a 1-year incidence of NRM of 37% (P = .02), a 1-year incidence of relapse of 25% (NS), a 1-year OS and PFS of 44% (P = .02), and 38% (P = .1), respectively, and a 1-year rate of death from GVHD or infection with GVHD of 31% (P = .04). In conclusion, our data suggest that HLA-mismatched NMA HCT with MSC coinfusion appeared to be safe.

Impact of Delirium on Distress, Health-Related Quality of Life, and Cognition 6 Months and 1 Year after Hematopoietic Cell Transplant - Corrected Proof

2010-01-25

Abstract: Delirium commonly occurs during myeloablative hematopoietic cell transplantation (HCT). Little is known about how delirium during the acute phase of HCT affects long-term distress, health-related quality of life (HRQOL), and neurocognitive functioning. This prospective, cohort study examines these outcomes at 6 months and 1 year in 90 patients undergoing HCT. Patients completed a battery assessing distress, HRQOL, and subjective neuropsychological functioning before receiving their first HCT as well as at 6 months and 1 year. Patients with a delirium episode within the 4 weeks after HCT had significantly more distress and fatigue at 6 months (P < .004) and at 1 year (P < .03), compared with patients without delirium. At 1 year, patients with delirium also had worse symptoms of depression and post traumatic stress (P < .03). Patients with delirium had worse physical health on the SF-12 at 6 months (P < .03) and worse mental health on the SF-12 at 1 year (P < .03). At both 6 months and 1 year, patients with delirium after HCT reported worse memory (P < .009) and executive functioning (P < .006). Delirium during the acute phase of HCT is significantly associated with persistent distress, decreased HRQOL, and subjective neurocognitive dysfunction at both 6 months and 1 year.

Tumor Necrosis Factor-α Gene Polymorphisms Are Associated with Severity of Acute Graft-Versus-Host Disease Following Matched Unrelated Donor Bone Marrow Transplantation in Children: A Pediatric Blood and Marrow Transplant Consortium Study - Corrected Proof

2010-01-25

Abstract: Tumor necrosis factor (TNF)-α plays a significant role in conditioning related toxicities and the development of acute graft-versus-host disease (aGVHD). TNF-α gene polymorphisms are associated with rejection after organ transplantation and aGVHD in matched related donor blood and marrow transplantation (BMT) recipients. Few studies have been published on unrelated donor BMT in the pediatric age group in this study, we examined the relationship between specific polymorphisms in TNF pathway genes and the occurrence and severity of aGVHD. Recipient single-nucleotide polymorphisms (SNPs) in TNF-α and TNF receptor superfamily members 1A (TNFRSF1A) and 1B (TNFRSF1B) were investigated. In a multi-institutional Pediatric Blood and Marrow Transplant Consortium trial, a total of 180 pediatric patients (mean age, 11.0 years) were prospectively evaluated for clinical outcomes after matched unrelated donor BMT. All patients received myeloablative conditioning and two-drug GVHD prophylaxis with cyclosporine or tacrolimus, with methotrexate in the majority of patients. TNF-α genotypes were not correlated with the overall incidence of aGVHD. Significant associations were seen between TNF-α variant alleles and the severity of aGVHD (grade II-IV and grade III-IV), especially when analyzed in whites only (n = 165). Grade II-IV aGVHD was correlated with recipient -857T allele (hazard ratio [HR], 0.47; P = .04), -238A allele (HR, 1.76; P = .002), and d3/d3 genotype (HR, 0.64; P = .03). Severe (grade III-IV) aGVHD was associated with TNF-α -1031C allele (HR, 2.38; P = .03), -863A allele (HR, 3.18; P = .003), and d4/d4 genotype (HR, 2.82; P = .01). After adjusting for clinical factors, the association of -1031C, -863A, -238A, and d4/d4 genotypes with severity of aGVHD remained statistically significant. No correlation between selected SNPs in TNFRSF1A or TNFRSF1B and the incidence or severity of aGVHD was found. Our findings indicate clinically important relationships between genetic polymorphisms in TNF-α and the severity of aGVHD in this cohort. Improved understanding of this relationship may allow for a risk-adjusted approach to GVHD prevention in pediatric BMT.

A Randomized Phase II Trial Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate for Acute Graft-versus-Host Disease Prophylaxis - Uncorrected Proof

2010-01-25

Abstract: Tacrolimus (Tac) plus methotrexate (MTX) is a standard regimen for graft-versus-host disease (GVHD) prophylaxis. Mycophenolate mofetil (MMF) is sometimes used instead of MTX to minimize toxicity, despite the lack of controlled studies demonstrating efficacy. We conducted a single-center, randomized phase II trial comparing Tac + MMF to Tac + MTX. Intent-to-treat analyses included 42 patients randomized to Tac + MMF and 47 to Tac + MTX. Patient characteristics were not different between the study arms. Patients in the Tac + MMF arm were less likely to experience severe mucositis, require narcotic analgesia and parenteral nutrition, and had earlier hospital discharge. The Tac + MMF arm had the same time to neutrophil recovery, but earlier platelet recovery. The cumulative incidence of grade II-IV acute GVHD (aGVHD) at 100 days was similar (P = .8), but grade III-IV aGVHD was higher in the Tac + MMF arm (19% versus 4%; P = .03); this was predominantly seen in unrelated donor transplants (26% versus 4%; P = .04), and less in related donor transplants (11% versus 4%; P = n.s.). Moderate or severe chronic GVHD was similar (P = .71). There were no significant differences between the arms in relapse, nonrelapse mortality, or overall and relapse-free survivals. MMF was associated with less early toxicity than MTX but was not as effective in preventing severe aGVHD, especially in unrelated donor transplants.

Glucocorticoid-Refractory Acute Graft-versus-Host Disease - Corrected Proof

Joseph Pidala, Claudio Anasetti — 2010-01-22

Abstract: Acute graft-versus-host disease (aGVHD) is a major cause of hematopoietic cell transplant (HCT) associated morbidity and mortality. Those who fail first-line therapy with ≥1 mg/kg of glucocorticoids achieve limited complete responses to salvage agents, and suffer inferior outcomes compared to those who respond to glucocorticoids. The literature to date in salvage therapy for refractory aGVHD suffers from a number of methodologic limitations, and the near absence of data on comparative effectiveness of alternative salvage agents limits conclusions and application to clinical practice. This review examines the current literature on salvage therapy for glucocorticoid-refractory aGVHD, identifies barriers to progress in the field, calls for consensus in definitions and response criteria in the conduct of refractory aGVHD trials, and explores the scientific and therapeutic implications of molecular insights into glucocorticoid responsiveness realized in allied investigation.

Dried Blood Spot Analysis: An Easy and Reliable Tool to Monitor the Biochemical Effect of Hematopoietic Stem Cell Transplantation in Hurler Syndrome Patients - Corrected Proof

2010-01-21

Abstract: Hurler syndrome (HS), the most severe phenotype in the spectrum of mucopolysaccharidosis type I, is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). At present, hematopoietic stem cell transplantation (HSCT) is the only treatment able to prevent disease progression in the central nervous system, and therefore considered the treatment of choice in HS patients. Because IDUA enzyme activities after HSCT have been suggested to influence the prognosis of HS patients, monitoring these activities after HSCT remains highly important. The use of dried blood spots (DBS) for enzyme analysis can be a useful alternative to the conventional leukocyte assay. Importantly, this method allows for convenient worldwide shipment, and can therefore be applied to monitor patients from larger areas of the world, or during large-scale international studies. Furthermore, this method requires only a minimal amount of blood. From 13 HS patients receiving HSCT, 36 paired whole blood and DBS samples were analyzed to assess leukocyte and DBS IDUA activities, respectively. To correct for potential interfering factors, simultaneous assay of the alpha-Galactosidase-A (AGA) activity was performed in the DBS samples and an IDUA/AGA ratio was calculated. A strong linear correlation was demonstrated between the DBS IDUA/AGA ratio and the leukocyte IDUA activity (r2 = .875, P < .001). This correlation was applicable to all enzyme activities, including the activities measured early after HSCT as well as heterozygous activities because of mixed chimerism or the use of a carrier donor. These results demonstrate that the DBS method is reliable to monitor the biochemical effect of HSCT in HS patients.

Emerging Role of CD20 Blockade in Allogeneic Hematopoietic Cell Transplantation - Corrected Proof

Mohamed A. Kharfan-Dabaja, Ali Bazarbachi — 2010-01-18

Abstract: There is growing evidence incriminating B lymphocytes in the pathogenesis of graft-versus-host disease (GVHD). Better understanding of the role of B lymphocytes has uncovered new therapeutic approaches, such as CD20 blockade, which appear to be improving outcomes in allogeneic hematopoietic cell transplant recipients. Administration of the chimeric murine/human anti-CD20 monoclonal antibody, rituximab, prior to hematopoietic cell allografting or as part of preparative regimens appears to reduce treatment-related mortality and to improve posttransplant outcomes mainly by decreasing the incidence and severity of acute GVHD. This beneficial effect of rituximab has not had an impact, to the same extent on the incidence of chronic GVHD, which remains a significant cause of morbidity and mortality following hematopoietic cell allografting. Alternatively, rituximab has been shown to be effective for treatment of cGVHD, but data is limited because of the lack of randomized controlled clinical trials and the small sample size in most of the published series. Incorporation of rituximab into the therapeutic armamentarium of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder has clearly improved the overall prognosis of this dreadful disease. This review highlights the evolving role of CD20 blockade in allogeneic hematopoietic cell transplantation and the need to continue to refine B cell depletion strategies in this setting.

Advancement of Pediatric Blood and Marrow Transplantation Research in North America: Priorities of the Pediatric Blood and Marrow Transplant Consortium - Corrected Proof

2010-01-15

Abstract: Advances in pediatric bone marrow transplantation (BMT) are slowed by the small number of patients with a given disease who undergo transplantation, a lack of sufficient infrastructure to run early-phase oncology protocols and studies of rare nonmalignant disorders, and challenges associated with funding multi-institutional trials. Leadership of the Pediatric Blood and Marrow Transplant Consortium (PBMTC), a large pediatric BMT clinical trials network representing 77 active and 45 affiliated centers worldwide, met in April 2009 to develop strategic plans to address these issues. Key barriers, including infrastructure development and funding, along with scientific initiatives in malignant and nonmalignant disorders, cellular therapeutics, graft-versus-host disease, and supportive care were discussed. The PBMTC's agenda for approaching these issues will result in infrastructure and trials specific to pediatrics that will run through the PBMTC or its partners, the Blood and Marrow Transplant Clinical Trials Network and the Children's Oncology Group.

Allogeneic Stem Cell Transplantation Using Myeloablative and Reduced-Intensity Conditioning in Patients with Major Histocompatibility Complex Class II Deficiency - Corrected Proof

2010-01-15

Abstract: Major histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Between June 1994 and February 2007, 30 children with MHC II deficiency underwent a total of 33 HSCT procedures. Median age at HSCT was 27 months. The stem cell source was unmanipulated bone marrow from HLA-identical related donors in 26 patients, one HLA antigen-mismatched bone marrow in 3 patients, and unrelated umbilical cord blood in 1 patient. Conditioning was with one of 3 myeloablative regimens—regimen A (18 patients): busulfan (Bu), cyclophosphamide (Cy), and etoposide; regimen B (2 patients): Bu, Cy, and antithymocyte globulin (ATG); or regimen C (1 patient): CY and total body irradiation (TBI)—or with a reduced-intensity regimen (12 patients): fludarabine, melphalan, and ATG. The median CD34 cell dose was 8.3 × 106/kg. Twenty patients experienced immune reconstitution and had sustained engraftment ranging from 9% to 100% for lymphoid lines and from 5% to 100% for myeloid lines that were significant to cure the disease. The overall disease-free survival rate was 66% and 76% after HLA-identical HSCT, with a median follow-up of 6.3 years, which is higher than previously reported. In HLA-identical transplant recipients, reliable donor stem cell engraftment and immune reconstitution were achieved through myeloablative or reduced-intensity conditioning. Further studies and long-term follow-up are needed to determine the appropriate conditioning regimen.

A Prospective Study of Iron Overload Management in Allogeneic Hematopoietic Cell Transplantation Survivors - Corrected Proof

Navneet S. Majhail, Hillard M. Lazarus, Linda J. Burns — 2010-01-15

Abstract: We report the results of a single-center, prospective evaluation for iron overload and subsequent treatment in 147 adult allogeneic hematopoietic cell transplantation (HCT) recipients who survived beyond 1 year after transplantation. Patients were screened by serum ferritin level; those with ferritin >1000 ng/mL underwent liver R2 magnetic resonance imaging to estimate liver iron concentration (LIC; normal ≤1.8 mg/g). Patients with significant iron overload (defined as LIC ≥5 mg/g), based on physician and patient preference, were offered observation only, phlebotomy, or enrollment in a pilot study of deferasirox. Sixteen patients had significant iron overload. Their median age was 51 years (range, 29-64 years), and they had survived a median of 21 months (range, 12-114 months). All 16 patients were transfusion-independent at study enrollment. Five patients received no treatment (median LIC, 6.4 mg/g; range, 5.1-28.3 mg/g), 8 underwent phlebotomy (median LIC, 13.1 mg/g; range, 7.8-43.0 mg/g), and 3 received daily deferasirox 20 mg/kg/day orally for 6 months (LIC, 6.3, 9.0, and 19.9 mg/g). Two patients had abnormal liver function tests, and 1 patient each had cirrhosis and unexplained congestive heart failure; all 4 of these patients underwent phlebotomy. Follow-up serum ferritin concentrations decreased spontaneously in 4 patients in the observation-only arm. Phlebotomy was generally well tolerated. Deferasirox also was well tolerated and led to decreased LIC after 6 months of therapy in all 3 patients. Phlebotomy is feasible in the majority of allogeneic HCT recipients who have survived for ≥1 year after HCT and have significant iron overload. Although the number of subjects is small, deferasirox may be a safe and effective alternative for allogeneic HCT survivors with iron overload who cannot undergo phlebotomy.

A Deletion Polymorphism in Glutathione-S-Transferase Mu (GSTM1) and/or Theta (GSTT1) Is Associated with an Increased Risk of Toxicity after Autologous Bone Marrow Transplantation - Corrected Proof

2010-01-14

Abstract: Toxicity after bone marrow transplantation (BMT) has interindividual variability that may be explained by common genetic polymorphisms in critical pathways. The glutathione-S-transferase (GST) isoenzymes detoxify the reactive oxygen species generated by chemotherapy agents and radiation. We investigated whether deletion polymorphisms in 2 GST genes (GSTM1 and GSTT1) were associated with toxicity after autologous or allogeneic BMT. The study population was selected from 699 consecutive BMT patients from 2 centers in Buffalo, NY, and Moscow, Russia, of whom 321 (203 autologous, 118 allogeneic BMT) had available banked samples and amplifiable DNA. Fifty percent of patients were homozygous null for GSTM1, which did not vary by center; however, the GSTT1 homozygous null deletion polymorphism occurred more frequently in patients treated in Moscow (38% versus 18%, P < .001). Overall grade 2-4 regimen-related toxicity occurred in 56%, with nearly 1 in 5 patients having 2 or more organ systems affected. Among autologous BMT patients, a deletion polymorphism in 1 or both genes was significantly associated with increased occurrence of overall toxicity (71% versus 56%, P = .034) and mucositis (74% versus 55%, P = .006). GSTM1 and/or GSTT1 deletion polymorphisms were not associated with toxicity after allogeneic BMT. Future studies may allow for individualized genetic risk stratification.

Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation in Patients Over 60 Years: Hematologic Malignancy Outcomes Are Not Impaired in Advanced Age - Corrected Proof

2010-01-13

Abstract: Reduced-intensity-conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is markedly underutilized in the elderly, in part because the impact of advanced age on outcomes is poorly understood. We retrospectively analyzed outcomes in 158 consecutive hematologic malignancy patients aged ≥60 years (median, 63 years; range: 60-71 years) undergoing fludarabine/busulfan-based RIC, with a median-follow-up of 34 months (range: 12.0-85.7). Multivariate analysis was undertaken for factors having an impact on outcome. For the patients aged ≥60 years, 2-year nonrelapse mortality (NRM) and relapse was 10% and 54.6%, respectively. Two-year overall and progression-free survival (OS, PFS) was 46% and 35%, respectively. Grade II-IV acute and chronic graft-versus-host disease (aGVHD, cGVHD) incidence was 19.6% and 45.9%, respectively. Comparing 110 patients aged 60-64 years versus 48 patients aged ≥65 years, 2-year NRM and relapse was 10.5% versus 8.3% (P = .84) and 53.5% versus 56.3% (P = .31), respectively. Grade II-IV aGVHD and cGVHD incidence was 19.1% versus 22.9% (P = .52) and 51.8% versus 32.5% (P = .01), respectively. Two-year OS and PFS was 49% versus 41% (P = .11) and 36% versus 35% (P = .24), respectively. In a multivariate Cox-model, high-risk disease associated with poorer PFS (hazard ratio [HR] = 2.1, P = .01) and OS (HR = 1.84, P = .03); acute myelogenous leukemia/myelodysplastic syndrome diagnosis (HR = 1.66, P = .03) and matched-related donor (HR = 1.62, P = .03) associated with poorer PFS. RIC HSCT is well tolerated, with reasonable survival in elderly patients. Age is not associated with impaired outcomes. HSCT should not be excluded solely based on advanced patient age.

Challenges in Hematopoietic Stem Cell Transplantation - Uncorrected Proof

Demetrios S. Theodoropoulos — 2010-01-11

The article by Gajewski et al. regarding projected shortages in physicians specialized in hematopoietic stem cell transplantation (HSCT) deals with issues of capital importance for the delivery of state-of-the-art medical care. The scope of HSCT keeps expanding, and will include a number of nonmalignant/nonhematologic disorders, as diverse (and yet as similar) as systemic lupus erythematosus and Crohn's disease. At the same time, the needs for traditional indications, such as thalassemia, are not being met. In the United States alone, up to 70,000 patients with sickle cell disease—only 1 of the current indications—could benefit from nonmyeloablative HSCT . The current rate of 18,000 procedures/year mentioned by the authors would prove a gross underestimate were HSCT to reach its full dimensions. Now, the anticipated undersupply of trained transplant specialists is expected to further aggravate the problem. Interestingly, this supply crisis comes at a time of amazing developments in the science of regenerative medicine, which, through cell reprogramming, not only promises to make HSCT as we know it today obsolete, but puts the therapeutic modalities of the whole specialty of hematology-oncology under a different perspective. Unfortunately, although science always finds a way to reset the standards of medicine, medicine has yet to find a simple way to absorb science. In a similar situation, the unprecedented growth of knowledge in molecular biology in the last 20 years determined the course of many an academic career but had a negligible impact on the early career choices of young physicians. In fact, the huge potential of such a wealth of knowledge was exploited, but too little, in the clinical practice of medicine. The shortcomings, however, of medicine have never stopped market forces from exerting their power or industries from taking advantage of scientific breakthroughs. In the case of molecular biology, the proverbial delay of clinicians to catch up with scientific progress led to the institution of a whole kind of medicine, the personalized medicine, which grows over and above the heads of the medical community. If hematology-oncology is not immune to similar manipulations, it could appear that not only the train of HSCT is about to be missed for lack of manpower, funds, and range, but the next 1, of regenerative medicine, may be missed too—and for the same reasons.

Plerixafor (Mozobil®) Alone to Mobilize Hematopoietic Stem Cells from Multiple Myeloma Patients for Autologous Transplantation - Corrected Proof

Neal Flomenberg, Raymond L. Comenzo, Karin Badel, Gary Calandra — 2010-01-11

Abstract: Rapid and durable recovery of hematopoietic function after hematopoietic stem cell transplantation (HSCT) requires the infusion of a sufficient number of hematopoietic stem cells (HSC). Granulocyte colony-stimulating factor (G-CSF), either alone or with chemotherapy, has been the traditional backbone of regimens used to mobilize HSC. Plerixafor (previously known as AMD3100), a selective antagonist of CXCR4, has recently been approved for autologous HSC mobilization in combination with G-CSF. The current study assessed the safety and efficacy of plerixafor as a single agent when given subcutaneously and followed by apheresis 6 hours later for the mobilization of HSC for transplantation in 9 patients with multiple myeloma (MM). All patients mobilized enough cells for at least 1 transplant, and demonstrated prompt recovery of hematopoietic function. Median time to engraftment was 10.5 days for neutrophils and 21 days for platelets. Significant adverse events were not observed. Recovery of peripheral blood cell counts was durable in all surviving patients. Despite these successes, mobilization with plerixafor alone was modest. However, in clinical circumstances where G-CSF or chemotherapy based-mobilization should not be used, mobilization with plerixafor alone may be required and effective. Further research into single agent use should focus on alternate route of administration as well as adjustment of the timing of the apheresis to improve cell HSC yield (ClinicalTrials.gov registration number: NCT00396383).

Hepatitis B Virus Reactivation and Efficacy of Prophylaxis with Lamivudine in Patients Undergoing Allogeneic Stem Cell Transplantation - Corrected Proof

2010-01-08

Abstract: Patients previously infected with hepatitis B virus (HBV) undergoing an allograft and recipients from HBV carrier donors are at risk of posttransplant viral reactivation. The role of prophylaxis with lamivudine remains unclear. One hundred seventeen patients, with a median age of 52 years (20-67 years), with various hematologic malignancies transplanted between 1999 and 2007 entered the study. Eighty-seven recipients negative for HBV surface antigen (HBsAg), antihepatitis B core antigen antibodies (anti-HBc), and HBV-DNA with HBsAg and HBV-DNA negative donors were defined as at low risk of HBV reactivation, whereas all the remaining 30 patients were defined as at high risk. Patients at high risk transplanted in 2005 or after received lamivudine to prevent HBV reactivation as per the Italian guidelines by the Associazione Italiana per lo Studio del Fegato (AISF). Patients at low risk did not experience HBV reactivation/hepatitis. Among the recipients at high risk, 11 of 25 anti-HBc positive, those HBsAg positive (2 of 2) or negative but transplanted from HBsAg positive donors (3 of 3) were treated with lamivudine. None of these developed HBV reactivation/hepatitis after a median follow-up of 40 months (17-55 months). Hepatitis developed in 3 anti-HBc positive untreated patients conditioned with a reduced-intensity regimen. Hepatitis B was not observed in recipients at low risk, transplanted from HBsAg negative/anti-HBc positive or negative donors. Lamivudine was effective in controlling reactivation in: HBsAg positive recipients, in patients transplanted from HBsAg positive donors and in HBsAg negative/antiHBc positive recipients, who showed a significant risk of reactivation if not given prophylaxis (NCT 00876148).