Biology of Blood and Marrow Transplantation

Peripheral Blood or Marrow: Is One Better Than the Other?

Mary Eapen — 2012-03-26

A study by Bertz et al. in this issue of Biology of Blood and Marrow Transplantation shows that the results of unrelated donor hematopoietic stem cell transplant for adults with acute myelogenous leukemia or myelodysplastic syndrome are better with transplantation of peripheral blood progenitor cells (PBPCs) compared to bone marrow (BM). Overall mortality risks were lower after transplantation of PBPC compared to BM. With a median follow-up of 10 years, event-free survival rate after PBPC transplants was 55% and significantly higher compared to 28% after BM transplants. This is in contrast to the findings of a randomized multicenter trial of unrelated donor PBPC vs BM for hematologic malignancies in North America . That trial randomized 273 patients to receive PBPC and 278 patients to receive BM. With a median follow-up of 3 years, event-free survival rates were not significantly different after PBPC and BM transplants, 47% and 44%, respectively . However, the incidence of chronic graft-versus-host disease (cGVHD) was more after transplantation of PBPC compared to BM grafts (53% vs 40%; P = .02) and without significant differences in non-relapse mortality rates between the 2 treatment groups . Bertz et al. also report more cGVHD after PBPC compared to BM transplants, but the observed difference was not statistically significant (52% vs 33%; P = .11). The probability estimates reported by Bertz et al. and Anasetti et al. are similar. Relatively few events in the small patient population in the report by Bertz et al. are the most likely explanation for their inability to detect statistically significant differences in cGVHD rates between the 2 graft sources.

Tandem Transplantation for Follicular Lymphoma: The Best of Both Worlds?

Ginna G. Laport — 2012-04-23

Follicular lymphoma (FL) is the second most common type of non-Hodgkin’s lymphoma with an incidence of ∼15,000 new cases/year in the United States. The definite management of patients with FL remains under considerable debate due to the numerous treatment options available today. Such options include observation, chemotherapy, external beam radiation therapy, monoclonal antibodies, and radioimmunoconjugates . Hematopoietic cell transplant (HCT) historically has been offered to younger patients and/or patients with fairly advanced disease. Autologous HCT (autoHCT) has unequivocally shown improved disease-free survival in patients with relapsed chemosensitive disease with 1 trial showing an overall survival benefit . For patients with FL with relapsed disease, retrospective analyses have shown that autoHCT can provide benefit for patients who are not heavily pretreated before autoHCT . There is no role for autoHCT as consolidation therapy in first remission as 3 randomized trials failed to demonstrate a survival advantage for autoHCT compared to conventional therapy .

Mesenchymal Stromal Cells: A New Tool against Graft-versus-Host Disease?

Frédéric Baron, Rainer Storb — 2011-09-29

Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti-inflammatory properties that prompted their clinical use as prevention and/or treatment for severe graft-versus-host disease (GVHD). Although a number of phase I-II studies have suggested that MSC infusion was safe and might be effective for preventing or treating acute GVHD, definitive proof of their efficacy remains lacking thus far. Multicenter randomized studies are ongoing to more precisely assess the impact of MSC infusion on GVHD prevention/treatment, whereas further research is performed in vitro and in animal models with the aims of determining the best way to expand MSCs ex vivo as well as the most efficient dose and schedule of MSCs administration. After introducing GVHD, MSC biology, and results of MSC infusion in animal models of allogeneic hematopoietic cell transplantation, this article reviews the results of the first clinical trials investigating the use of MSC infusion as prevention or treatment of GVHD.

Graft-versus-Host Disease–Related Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15–Positive Target Cells

Qian Zhan, Robert Korngold, Cecilia Lezcano, Frank McKeon, George F. Murphy — 2012-04-01

Acute graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation, involves cytotoxic soluble and cellular effectors that selectively induce apoptosis in normally apoptosis-resistant, cytokeratin 15 (K15)-expressing epithelial stem cells residing at the tips of rete ridges of human epidermis and in analogous rete-like prominences (RLPs) of murine dorsal lingual epithelium. The mechanisms whereby epithelial stem cells are rendered vulnerable to apoptosis during allostimulation are unknown. We hypothesized that GVHD-induced target cell injury may be related to pathways involving the p53 family that are constitutively expressed by epithelial stem cells and designed to trigger physiological apoptosis as a result of environmental danger signals. Among the p53 family members, we found that p73 protein and mRNA were preferentially expressed in K15+ RLPs of murine lingual squamous epithelium. On in vitro exposure to recombinant TNF-α and IL-1 in an organ culture model previously shown to replicate early GVHD-like target cell injury, apoptosis was selectively induced in K15+ stem cell regions and was associated with induction of phosphorylated p73, a marker for p73 activation, and apoptosis was abrogated in target tissue obtained from p73-deficient (p73−/−) mice. Evaluation of early in vivo lesions in experimental murine GVHD disclosed identical patterns of phosphorylated p73 expression that coincided with the onset of effector T cell infiltration and target cell apoptosis within K15+ RLPs. This study is the first to suggest that paradoxical apoptosis in GVHD of physiologically protected K15+ epithelial stem cells is explainable, at least in part, by cytokine-induced activation of suicide pathways designed to eliminate stem cells after exposure to deleterious factors perceived to be harmful to the host.

Allogeneic Hematopoietic Stem Cell Transplantation for Philadelphia-Positive Acute Lymphoblastic Leukemia in Children and Adolescents: A Retrospective Multicenter Study of the Italian Association of Pediatric Hematology and Oncology (AIEOP)

2011-10-21

Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) still represents a major challenge. We report the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP) with allogeneic hematopoietic stem cell transplantation (HSCT) in children with Ph+ ALL from 1990 to 2008. Sixty-nine patients received HSCT from either a related (37, 54%) or an unrelated (32, 46%) donor. Twenty-five patients (36%) underwent transplantation before 2000 and 44 (64%) after 2000. Twenty-three patients (33%) received Imatinib mesylate treatment before HSCT and seven (10%) after HSCT. After a median follow-up of 56 months, the overall survival (OS) probability was 51% (95% confidence interval [CI], 38-63), the leukemia-free survival (LFS) was 47% (95% CI, 34-59), transplantation-related mortality (TRM) was 17% (95% CI, 10-30), and relapse incidence (RI) was 36% (95% CI, 26-50). Transplantation in first complete remission, female gender, and lower WBC count at diagnosis were associated with a better LFS in both univariate and multivariate analyses. Patients with p210 transcript had a trend for a worse prognosis compared with those who had the p190 transcript. Our series confirms the role of HSCT in the eradication of Ph+ ALL. Early HSCT is recommended once morphologic remission is obtained.

Outcomes of Allogeneic Hematopoietic Cell Transplantation for Adolescent and Young Adults Compared with Children and Older Adults with Acute Myeloid Leukemia

2011-10-31

Adolescents and young adults (AYAs) with cancer have not experienced improvements in survival to the same extent as children and older adults. We compared outcomes among children (<15 years), AYAs (15-40 years) and older adults (>40 years) receiving allogeneic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML). Our cohort consisted of 900 children, 2,708 AYA, and 2,728 older adult recipients of HLA-identical sibling or unrelated donor (URD) transplantation using myeloablative or reduced-intensity/nonmyeloablative conditioning. Outcomes were assessed over three time periods (1980-1988, 1989-1997, 1998-2005) for siblings and two time periods (1989-1997, 1998-2005) for URD HCT. Analyses were stratified by donor type. Results showed overall survival for AYAs using either siblings or URD improved over time. Although children had better and older adults had worse survival compared with AYAs, improvements in survival for AYAs did not lag behind those for children and older adults. After sibling donor HCT, 5-year adjusted survival for the three time periods was 40%, 48%, and 53% for children, 35%, 41%, and 42% for AYAs, and 22%, 30%, and 34% for older adults. Among URD HCT recipients, 5-year adjusted survival for the two time periods was 38% and 37% for children, 24% and 28% for AYAs, and 19% and 23% for older adults. Improvements in survival occurred because of a reduction in risk of treatment-related mortality. The risk of relapse did not change over time. Improvements in survival among AYAs undergoing allogeneic HCT for AML have paralleled those among children and older adults.

Risk Factors for 30-Day Hospital Readmission following Myeloablative Allogeneic Hematopoietic Cell Transplantation (allo-HCT)

2011-10-31

Patient readmission within 30 days from discharge has been perceived by the Centers for Medicare and Medical Services as an indicator of poor healthcare quality for specific high-cost medical conditions. Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are often being readmitted. Our study identified the risk factors for 30-day readmission among 618 adult recipients of myeloablative allo-HCT from 1990 to 2009. Two hundred forty-two (39%) of 618 patients (median age = 42 years [range: 18-66]) were readmitted a median of 10 days (range: 1-30) from their hospital discharge. Median duration of readmission was 8 days (range: 0-103). Infections (n = 68), fever with or without identified source of infection (n = 63), gastrointestinal complications (n = 44), graft-versus-host disease (GVHD) (n = 38), and other reasons (n = 29) accounted for 28%, 26%, 18%, 16%, and 12% of readmissions, respectively. During their index admission, patients who were subsequently readmitted had more documented infections (P < .001), higher hematopoietic cell transplantation comorbidity index (HCT-CI) (P < .01), total body irridiation (TBI)-based conditioning (P < .001), unrelated donor (P < .001), and peripheral stem cell (P = .014) transplantation. In multivariable analysis, HCT-CI (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.25-2.52), TBI-based preparative regimen (OR = 2.63; 95% CI, 1.67-4.13), and infection during admission for allo-HSCT (OR = 2.00; 95% CI, 1.37-2.92) predicted 30-day readmission. Thirty-day readmission itself was an independent predictor of all-cause mortality (hazard ratio [HR]Adj = 1.66; 95% CI, 1.36-2.10). Our data emphasize the importance of a risk-standardized approach to 30-day hospital readmission if it is used as a quality-of-care metric for bone marrow transplantation.

Risk Factors for Progression from Cytomegalovirus Viremia to Cytomegalovirus Disease after Allogeneic Hematopoietic Stem Cell Transplantation

2011-11-07

Cytomegalovirus (CMV) disease is a major cause of infectious complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although patients undergoing allo-HSCT receive prophylactic and preemptive treatment for CMV, a subset of patients experience clinically significant CMV disease. This study investigated the risk factors for progression from CMV viremia to CMV disease during or after preemptive therapy in patients undergoing allo-HSCT. Between January 2006 and August 2010, 43 patients received preemptive therapy for CMV viremia after allo-HSCT. These patients experienced 74 episodes of CMV viremia. Nine of the patients (21%) and 12 of the episodes (16%) progressed to CMV disease. Univariate analysis identified several risk factors for progression to CMV disease, including high initial viral load (P = .020), leukopenia (P = .012), and neutropenia (P = .033) at the time of detection of CMV viremia. On multivariate analysis, leukopenia remained an independent predictor (hazard ratio, 4.347; P = .045). The rate of failure to clear CMV viremia after 1 cycle of preemptive therapy was higher in the leukopenia group than in the non-leukopenia group (60.0% versus 16.9%; P = .002). This indicates that leukopenia initially documented with CMV viremia is related to lower viral response to preemptive therapy and is a notable risk factor for progression from CMV viremia to CMV disease.

CD3+/Tregs Ratio in Donor Grafts Is Linked to Acute Graft-versus-Host Disease and Immunologic Recovery after Allogeneic Peripheral Blood Stem Cell Transplantation

2011-11-07

Graft-versus-host disease (GVHD), mediated by mature T cells present in the donor graft, remains a major complication after allogeneic peripheral blood stem cell transplantation (PBSCT). Regulatory T cells (Tregs) (CD4+CD25highFoxp3+) are believed to maintain tolerance and to inhibit GVHD after allogeneic PBSCT (allo-PBSCT). In this study, we analyzed the graft CD3+/Tregs ratio (gCD3/Tregs R) and evaluated its impact on acute GVHD (aGVHD) and immunologic recovery after myeloablative allo-PBSCT. We analyzed 65 consecutive patients who underwent transplantation with unmanipulated peripheral blood stem cells from an HLA-identical related donor (n = 45) or an HLA-identical unrelated donor (n = 20). The median CD3+ and Tregs doses administered were 256 × 106/kg of body weight (range, 67-550 × 106/kg) and 12 × 106/kg (range, 2-21 × 106/kg), respectively; the median gCD3/Tregs R value was 18 (range, 8-250). Patients were subdivided into a high gCD3/Tregs R (≥36) group (HR; n = 26) and a low gCD3/Tregs R (<36) group (LR; n = 39). The incidence of aGVHD (grade II-IV) was lower in the LR group compared with the HR group (8/39 [20%] versus 22/26 [84%]; P < .001). Median cytomegalovirus-specific CD8+ T lymphocytes were significantly higher in the LR group than in the HR group at 1 month (2 cells/μL versus 0 cells/μL; P < .001), 2 months (6 cells/μL versus 1 cell/μL; P < .001), and 3 months (15 cells/μL versus 3 cells/μL; P < .001) months. Moreover, cytomegalovirus infection/disease was observed in 15% of patients in the LR group versus 69% of patients in the HR group (P < .001). At multivariate logistic regression, gCD3/Tregs R was correlated both with aGVHD (odds ratio, 2.50; 95% confidence interval, 1.30-4.50; P = .05) and with cytomegalovirus infection/disease (odds ratio, 2.35; 95% confidence interval, 0.9-5.00; P = .05). Taken together, our data may suggest that the balance in favor of graft Tregs content is able to mediate protective effects against aGVHD and to maintain an optimal microenviroment for the reconstitution of functional immunity.

Marrow versus Blood-Derived Stem Cell Grafts for Allogeneic Transplantation from Unrelated Donors in Patients with Active Myeloid Leukemia or Myelodysplasia

2011-11-21

Peripheral blood stem cells (PBSCs) are increasingly used as the graft source in allogeneic hematopoietic cell transplantation. We compared long-term outcome after unrelated donor transplantation of 85 consecutive patients with acute myelogenous leukemia or myelodysplastic syndrome regarding disease status (early disease [CR1, refractory anemia); n = 25 and advanced/active disease [>CR1, >refractory anemia]; n = 60) who were treated with conventional conditioning regimens followed by bone marrow (BM) or PBSC grafts. Graft-versus-host disease prophylaxis consisted mainly of cyclosporine A, short-course methotrexate, and anti-T-lymphocyte globulin. After a median follow-up of 118 months (68-174), the 10-year event-free survival rate after peripheral blood stem cell transplantation (PBSCT) was 54.8% (95% confidence interval [CI], 39.7%-69.8%), and after bone marrow transplantation (BMT), it was 27.9% (14.5%-41.3%; P < .004). In the advanced/active disease group, the 10-year event-free survival rate after PBSCT was 50% (30.8%-69.2%), and after BMT, it was 23.5% (9.3%-37.8%; P < .007). Non relapse mortality was less after PBSCT than BMT (14.3% vs 30.2%), respectively. In multivariate Cox regression analysis, PBSCT showed a better overall survival (OS; hazard ratio [HR], 0.43; 95% CI, 0.23-0.79; P = .007) compared to BMT; unfavorable/unknown prognostic impact cytogenetic abnormalities were an adverse factor for all patients (HR, 2.202; 95% CI, 1.19-4.06; P = .011). In patients with advanced disease, the use of PBSCs showed a significant favorable outcome via multivariate analysis (HR, 0.49; 95% CI, 0.24-0.99; P = .046). Outcome of acute myelogenous leukemia/myelodysplastic syndrome after unrelated hematopoietic cell transplantation is adversely affected by cytogenetic abnormalities and state of remission at hematopoietic cell transplantation. PBSC as a graft source has a significant favorable influence on survival.

Relationship of Race/Ethnicity and Survival after Single Umbilical Cord Blood Transplantation for Adults and Children with Leukemia and Myelodysplastic Syndromes

2011-11-07

The relationship of race/ethnicity with outcomes of umbilical cord blood transplantation (UCBT) is not well known. We analyzed the association between race/ethnicity and outcomes of unrelated single UCBT for leukemia and myelodysplastic syndromes. Our retrospective cohort study consisted of 885 adults and children (612 whites, 145 blacks, and 128 Hispanics) who received unrelated single UCBT for leukemia and myelodysplastic syndromes between 1995 and 2006 and were reported to the Center for International Blood and Marrow Transplant Research. A 5-6/6 HLA-matched unit with a total nucleated cell count infused of ≥2.5 × 107/kg was given to 40% white and 42% Hispanic, but only 21% black patients. Overall survival at 2 years was 44% for whites, 34% for blacks, and 46% for Hispanics (P = .008). In multivariate analysis adjusting for patient, disease, and treatment factors (including HLA match and cell dose), blacks had inferior overall survival (relative risk of death, 1.31; P = .02), whereas overall survival of Hispanics was similar (relative risk, 1.03; P = .81) to that of whites. For all patients, younger age, early-stage disease, use of units with higher cell dose, and performance status ≥80 were independent predictors of improved survival. Black patients and white patients infused with well-matched cords had comparable survival; similarly, black and white patients receiving units with adequate cell dose had similar survival. These results suggest that blacks have inferior survival to whites after single UCBT, but outcomes are improved when units with a higher cell dose are used.

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation

2011-11-10

We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m2 × 5, melphalan 140 mg/m2 × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.

Evaluation of Oral Beclomethasone Dipropionate for Prevention of Acute Graft-versus-Host Disease

2011-11-10

Results from two randomized trials have shown that oral beclomethasone dipropionate (BDP) is effective for treatment of acute gastrointestinal graft-versus-host disease. Here, we report results of a double-blind, randomized placebo-controlled phase II study designed to test the hypothesis that acute graft-versus-host disease could be prevented by administration of oral BDP, beginning before hematopoietic cell transplantation and continuing until day 75 after hematopoietic cell transplantation after myeloablative conditioning. Study drug (BDP or placebo) was administered as 1-mg immediate-release formulation plus 1-mg delayed-release formulation orally four times daily. According to the primary endpoint, systemic glucocorticoid treatment for graft-versus-host disease was given to 60 of the 92 participants (65%) in the BDP arm, versus 31 of 46 participants (67%) in the placebo arm. The secondary efficacy endpoints showed no statistically significant differences between the two arms. The proportion of participants who took at least 90% of the prescribed study drug during the first 4 weeks after hematopoietic cell transplantation was 54% overall. Lower severity of mucositis strongly correlated with higher adherence to the schedule of study drug administration. Inconsistent adherence related to mucositis during recovery after myeloablative conditioning may have obscured a beneficial therapeutic effect in the current study.

Impact of Bone Marrow Hematogones on Umbilical Cord Blood Transplantation Outcomes in Patients with Acute Myeloid Leukemia

2011-11-21

Early after umbilical cord blood transplantation, patients show marked differences in bone marrow (BM) hematogone percentages. Little is known about whether these differences are clinically relevant. We hypothesized that early recovery of hematogones may be associated with improved transplantation outcomes. BM aspirates were assessed from 88 patients with acute myeloid leukemia by two independent reviewers at day 21 and 100 after umbilical cord blood transplantation. Interobserver variability for BM hematogone percentages at these time points showed correlation coefficients of 0.83 and 0.98, respectively (P ≤ .01 for both). A high percentage of hematogones at day 21 was associated with less acute graft-versus-host disease grade 3 to 4 (P = .01). At day 100, a high percentage of BM hematogones was associated with improved overall survival (P = .02) and lower treatment-related mortality (P ≤ .01). This study shows that BM hematogone percentages may be useful prognostic indicators in patients with acute myeloid leukemia after umbilical cord blood transplantation and should be routinely reported in BM differential counts.

T Cell–Depleted Partial Matched Unrelated Donor Transplant for Advanced Myeloid Malignancy: KIR Ligand Mismatch and Outcome

2011-12-08

To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cell alloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M2/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5 patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.

Highly Variable Pharmacokinetics of Once-Daily Intravenous Busulfan When Combined with Fludarabine in Pediatric Patients: Phase I Clinical Study for Determination of Optimal Once-Daily Busulfan Dose Using Pharmacokinetic Modeling

2011-12-08

Busulfan has a narrow therapeutic range, and in children, pharmacokinetic variability has been found to be high even after the use of intravenous (i.v.) busulfan. Recently, a reduced toxicity myeloablative regimen showed promising results, but the data of busulfan pharmacokinetics in hematopoietic stem cell transplantation (HSCT) using a targeted busulfan/fludarabine regimen in children has not yet been reported. We performed therapeutic drug monitoring (TDM) after once-daily i.v. busulfan combined with fludarabine and analyzed the outcomes. Busulfan (i.v.) was administered once daily for 4 consecutive days. The daily target area under the curve (AUC) was 18,125-20,000 μg∗h/L/day (4415-4872 μmol∗min/L/day), which was reduced to 18,000-19,000 μg∗h/L/day (4384-4628 μmol∗min/L/day) after a high incidence of toxicity was observed. A total of 24 patients were enrolled. After infusion of busulfan on the first day, patients showed AUC that ranged from 12,079 to 31,660 μg∗h/L (2942 to 7712 μmol∗min/L) (median 16,824 μg∗h/L, percent coefficient of variation (%CV) = 26.5%), with clearance of 1.74-6.94 mL/min/kg (median 4.03 mL/min/kg). We performed daily TDM in 20 patients, and during the daily TDM, the actual AUC ranged from 73% to 146% of the target AUC, showing high intraindividual variability. The %CV of busulfan clearance of each individual ranged from 7.7% to 38.7%. The total dose of busulfan administered for 4 days ranged from 287.3 mg/m2 to 689.3 mg/m2. Graft failure occurred in 3 patients with total AUC less than 74,000 μg∗h/L (18,026 μmol∗min/L), and 2 patients with relatively high total AUC experienced veno-occlusive disease. Busulfan pharmacokinetics showed high inter- and intraindividual variability in HSCT using a targeted busulfan/fludarabine regimen, which indicates the need for intensive monitoring and dose adjustment to improve the outcome of HSCT. Currently, we are performing a newly designed phase II study to decrease regimen-related toxicities and reduce graft failure by setting an optimal target AUC based on this study.

Tandem Autologous–Allogeneic Nonmyeloablative Sibling Transplantation in Relapsed Follicular Lymphoma Leads to Impressive Progression-Free Survival with Minimal Toxicity

2011-12-08

Autologous stem cell transplantation (ASCT) prolongs survival in patients with relapsed follicular lymphoma. ASCT is usually not curative, however. Myeloablative allogeneic transplantation has produced long-term survival at a cost of significant transplantation-related mortality (TRM), whereas reduced-intensity transplantation entails less TRM but has a higher relapse rate. We thus initiated a protocol consisting of ASCT followed by nonmyeloablative allogeneic transplantation (NMT) for relapsed follicular lymphoma to mimic myeloablative allogeneic transplantation without the associated toxicity. The NMT was non–T cell-depleted, and all donors were HLA-identical siblings. We report results in 27 patients with a median age of 49 years (range, 34-65 years). Five patients demonstrated histological progression toward an aggressive lymphoma. The patients had received a median of 3 lines of previous therapy. Disease status before ASCT included 8 patients in complete remission, 14 in partial remission, and 5 refractory. Five patients developed grade II-IV acute graft-versus-host disease, and 20 patients developed chronic graft-versus-host disease requiring systemic therapy. With a median follow-up of 39 months after NMT, overall survival and progression-free survival were 96% at 3 years. We conclude that the combined ASCT-NMT strategy appears to be safe, with excellent progression-free survival even in refractory and transformed cases. This novel approach warrants further investigation in larger prospective studies.

Toll-Like 4 Receptor Variant, Asp299Gly, and Reduced Risk of Hemorrhagic Cystitis after Hematopoietic Stem Cell Transplantation

2012-02-10

Hemorrhagic cystitis (HC) is a major cause of morbidity after hematopoietic stem cell transplantation. Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system and induces inflammation. Individuals with the single nucleotide polymorphisms Thr399Ile (rs4986791) or Asp299Gly (rs4986790) of TLR4 show diminished inflammatory responsiveness to endotoxins. The genotype of TLR4 was determined in 166 children who underwent allogeneic hematopoietic stem cell transplantation and in their donors. Asp299Gly was present in 21 patients (13%) and 24 donors (14%). Thr399Ile was found in 22 patients (13%) and 25 donors (15%). The incidence of HC was significantly lower in patients with Asp299Gly (0% vs 23%; P = .009) and in patients who underwent transplantation from a donor with Asp299Gly (4% vs 23%; P = .05). The trend was the same for Thr399Ile—donor positive (8% vs 22%; P = .17), recipient positive (9% vs 22%; P = .25), donor or recipient positive (8% vs 23%; P = .04). Multivariate analysis revealed age, conditioning with busulfan, and absence of Asp299Gly as independent risk factors for HC. In conclusion, the TLR4 Asp299Gly variant seems to confer protection against hemorrhagic cystitis. This study provides the first indication that the innate immune system through TLR4 signaling pathway plays a role in the pathogenesis of HC after hematopoietic stem cell transplantation.

Unrelated Cord Blood Transplantation in Adult and Pediatric Acute Lymphoblastic Leukemia: Effect of Minimal Residual Disease on Relapse and Survival

2012-03-19

Data on pretransplantation minimal residual disease (MRD) and outcomes of umbilical cord blood transplantation (UCBT) are limited. Out of the 143 patients with acute lymphoblastic leukemia (ALL) who underwent UCBT at the University of Minnesota between 2004 and 2010, we evaluated 86 patients with available MRD assessment data by 4- and 8-color flow cytometry analysis immediately before transplantation. Ten patients (11.6%) were MRD-positive, and 76 were MRD-negative (88.4%). Most of the patients (82%) received myeloablative conditioning. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. In multivariate analysis, age, disease status (complete remission [CR] 1 versus CR2/CR3), disease group (precursor B cell ALL versus Philadelphia chromosome–positive ALL versus T cell ALL), and time to transplantation had no impact on relapse. Patients with MRD before UCBT had a greater incidence of relapse at 2 years (relapse rate, 30%; 95% confidence interval [CI], 4%-56%) and lower 3-year disease-free survival (30%; 95% CI, 7%-58%) compared with those without MRD (relapse rate, 16%; 95% CI, 8%-25%; P = .05; disease-free survival, 55%; 95% CI, 43%-66%; P = .02). Our data suggest that in patients with ALL, achieving an MRD-negative state before UCBT improves outcomes.

Bone Marrow B cell Precursor Number after Allogeneic Stem Cell Transplantation and GVHD Development

2012-03-22

Patients without chronic graft-versus-host disease (cGVHD) have robust B cell reconstitution and are able to maintain B cell homeostasis after allogeneic hematopoietic stem cell transplantation (HSCT). To determine whether B lymphopoiesis differs before cGVHD develops, we examined bone marrow (BM) biopsies for terminal deoxynucleotidyl transferase (TdT) and PAX5 immunostaining early post-HSCT at day 30 when all patients have been shown to have high B cell activating factor (BAFF) levels. We found significantly greater numbers of BM B cell precursors in patients who did not develop cGVHD compared with those who developed cGVHD (median = 44 vs 2 cells/high powered field [hpf]; respectively; P < .001). Importantly, a significant increase in precursor B cells was maintained when patients receiving high-dose steroid therapy were excluded (median = 49 vs 20 cells/hpf; P = .017). Thus, we demonstrate the association of BM B cell production capacity in human GVHD development. Increased BM precursor B cell number may serve to predict good clinical outcome after HSCT.

Masthead (Purpose and Scope)

2012-06-01

Editorial Board

2012-06-01

Officers and Directors of ASBMT

2012-06-01

Biology of Blood and Marrow Transplantation

Peripheral Blood or Marrow: Is One Better Than the Other?

Tandem Transplantation for Follicular Lymphoma: The Best of Both Worlds?

Mesenchymal Stromal Cells: A New Tool against Graft-versus-Host Disease?

Graft-versus-Host Disease–Related Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15–Positive Target Cells

Allogeneic Hematopoietic Stem Cell Transplantation for Philadelphia-Positive Acute Lymphoblastic Leukemia in Children and Adolescents: A Retrospective Multicenter Study of the Italian Association of Pediatric Hematology and Oncology (AIEOP)

Outcomes of Allogeneic Hematopoietic Cell Transplantation for Adolescent and Young Adults Compared with Children and Older Adults with Acute Myeloid Leukemia

Risk Factors for 30-Day Hospital Readmission following Myeloablative Allogeneic Hematopoietic Cell Transplantation (allo-HCT)

Risk Factors for Progression from Cytomegalovirus Viremia to Cytomegalovirus Disease after Allogeneic Hematopoietic Stem Cell Transplantation

CD3+/Tregs Ratio in Donor Grafts Is Linked to Acute Graft-versus-Host Disease and Immunologic Recovery after Allogeneic Peripheral Blood Stem Cell Transplantation

Marrow versus Blood-Derived Stem Cell Grafts for Allogeneic Transplantation from Unrelated Donors in Patients with Active Myeloid Leukemia or Myelodysplasia

Relationship of Race/Ethnicity and Survival after Single Umbilical Cord Blood Transplantation for Adults and Children with Leukemia and Myelodysplastic Syndromes

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation

Evaluation of Oral Beclomethasone Dipropionate for Prevention of Acute Graft-versus-Host Disease

Impact of Bone Marrow Hematogones on Umbilical Cord Blood Transplantation Outcomes in Patients with Acute Myeloid Leukemia

T Cell–Depleted Partial Matched Unrelated Donor Transplant for Advanced Myeloid Malignancy: KIR Ligand Mismatch and Outcome

Highly Variable Pharmacokinetics of Once-Daily Intravenous Busulfan When Combined with Fludarabine in Pediatric Patients: Phase I Clinical Study for Determination of Optimal Once-Daily Busulfan Dose Using Pharmacokinetic Modeling

Tandem Autologous–Allogeneic Nonmyeloablative Sibling Transplantation in Relapsed Follicular Lymphoma Leads to Impressive Progression-Free Survival with Minimal Toxicity

Toll-Like 4 Receptor Variant, Asp299Gly, and Reduced Risk of Hemorrhagic Cystitis after Hematopoietic Stem Cell Transplantation

Unrelated Cord Blood Transplantation in Adult and Pediatric Acute Lymphoblastic Leukemia: Effect of Minimal Residual Disease on Relapse and Survival

Bone Marrow B cell Precursor Number after Allogeneic Stem Cell Transplantation and GVHD Development

Masthead (Purpose and Scope)

Editorial Board

Officers and Directors of ASBMT

Table of Contents