Biology of Blood and Marrow Transplantation

New Hope for Mobilization Failures . . . Again

John F. DiPersio — 2011-12-21

Patients undergoing peripheral blood stem cell mobilization for autologous transplantation may fail to achieve the generally accepted minimum threshold for transplantation (≥2 × 106 CD34/kg) despite using optimal doses of granulocyte-colony stimiulating factor (G-CSF) or chemotherapy plus G-CSF. Failure rates vary from center to center but are felt to be highest in certain diseases such as non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease (HD), and in heavily pretreated patients with multiple myeloma (MM). Although there is both vigorous debate and varying understanding of the optimal methods for mobilization (G-CSF alone versus chemotherapy plus G-CSF) there is general agreement that these diseases and various risk factors are associated with high rates of stem cell collection failure. The known risk factors include age, high-risk diseases such as lymphoma, progressive disease, bone marrow involvement, previous radiation therapy, premobilization platelet counts, exposure to repetitive cycles of chemotherapy with specific chemotherapies such as fludarabine and biologic therapies such as lenalidomide (>3-6 cycles). There are likely other risk factors that are either poorly understood (SDF-1 and CXCR4 single nucleotide polymorphisms, sympathetic nervous system function, and innervation of the bone marrow) or not yet identified (diabetes, germ line polymorphisms in genes that control stem cell quiescence and mass) . Because the SDF-1/CXCR4 axis is critical for stem cell trafficking and homing any agent that modulates this axis or interrupts this ligand-receptor interaction would be expected to promote stem cell trafficking from the bone marrow to the peripheral blood yielding enhanced stem cell collections.

My AML Cytogenetics Classification Scheme Is Better Than Yours

Mikkael A. Sekeres — 2011-12-08

Growing up in Rhode Island, my brother and I spent hours – I mean, hours – in the schoolyard around the block from our house arguing over which baseball team was better: the Yankees or the Red Sox. I rooted for the Yankees, just like my father and his father, while my brother, the second born, favored the Sox. This was the late 1970s, and we compared player to player (Jackson vs Rice, Guidry vs Tiant), position to position, tirelessly trying to convince the other, based on the past performance of our teams, which was superior, and each of us leaving the quarrel convinced the other was a complete idiot.

NCI, NHLBI/PBMTC First International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Health-Related Quality of Life, Functional, and Neurocognitive Outcomes

2011-12-12

The purpose of this manuscript is to summarize issues relevant to health-related quality of life (HRQL), physical function, and neurocognitive function for survivors of pediatric hematopoietic stem cell transplantation (HCT). The physiologic and psychological demands of HCT and its sequelae have the potential to substantially alter HRQL. When compared with research on adult HCT recipients, research in pediatric HRQL following HCT has lagged considerably. Initially, this lag was because of limited validated questionnaires, small numbers of affected patients, and a general lack of salience for the topic relative to traditional endpoints, such as transplant-related toxicity and potential mortality. The percentage of childhood HCT survivors with physical disability ranges from 7% to 17% in studies where the outcome was based on clinician or self-report measures, to over 40% in studies where the outcome was based on a directly measured physical performance task. Direct and comprehensive measures of physical performance may help further clarify the proportion of individuals who have subclinical problems amenable to intervention before apparent functional loss becomes a problem. There is a need to include longer term survivors in such an assessment. In terms of neurocognitive function, the majority of reports demonstrate relatively good function in survivors. However, it is clear that little or no data on outcomes beyond 5 years posttransplant have been obtained, and clinicians working with this population remain concerned regarding the cognitive functions of these survivors. Research focused on these domains should attempt to better understand the prevalence of the problem using child self-report and direct measurements of function, standardize measurement methods, and tools across trials, obtain longer term evaluations and begin to consider interventional trials.

The National Marrow Donor Program’s Symposium on Hematopoietic Cell Transplantation in 2020: A Health Care Resource and Infrastructure Assessment

2011-12-16

Hematopoietic cell transplantation (HCT) is the only known curative therapy for many patients with life-threatening hematologic and oncologic diseases. It is estimated that the National Marrow Donor Program® (NMDP) will facilitate 10,000 transplants by 2015, double the current number. To better understand the existing personnel and center infrastructure for HCT in the country and to address system capacity challenges to the future growth of HCT, the NMDP convened a diverse group of stakeholders and thought leaders representing HCT physicians, physician assistants, nurse practitioners, nurses, pharmacists, other healthcare providers, HCT program directors, hospital administrators, payors, and professional organizations. Working groups were formed to identify: capacity issues because of shortages in human resources, structural constraints, and patient access barriers including diversity and healthcare disparity challenges; recommendations to address challenges; and stakeholders to engage. This report details the deliberations and recommendations of a national symposium, “Hematopoietic Cell Transplantation in 2020: A Health Care Resource and Infrastructure Assessment,” held in September 2010.

Easy-to-Read Informed Consent Forms for Hematopoietic Cell Transplantation Clinical Trials

2011-08-01

Informed consent is essential to ethical research and is requisite to participation in clinical research. Yet most hematopoietic cell transplantation (HCT) informed consent forms (ICFs) are written at reading levels that are above the ability of the average person in the United States (U.S.). The recent development of ICF templates by the National Cancer Institute, National Institutes of Health, and the National Heart Blood and Lung Institute have not resulted in increased patient comprehension of information. Barriers to creating Easy-to-Read ICFs that meet U.S. federal requirements and pass institutional review board (IRB) review are the result of multiple interconnected factors. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) formed an ad hoc review team to address concerns regarding the overall readability and length of ICFs used for BMT CTN trials. This paper summarizes recommendations of the review team for the development and formatting of Easy-to-Read ICFs for HCT multicenter clinical trials, the most novel of which is the use of a 2-column format. These recommendations intend to guide the ICF writing process, simplify local IRB review of the ICF, enhance patient comprehension, and improve patient satisfaction. The BMT CTN plans to evaluate the impact of the Easy-to-Read format compared with the traditional format on the informed consent process.

The Pretransplantation Serum Cytokine Profile in Allogeneic Stem Cell Recipients Differs from Healthy Individuals, and Various Profiles are Associated with Different Risks of Posttransplantation Complications

2011-10-21

Cytokines play a key role in regulation of normal and malignant hematopoiesis, angiogenesis, and inflammation. Serum levels of several cytokines are altered in patients with hematologic malignancies, and pretransplant cytokine levels seem to have a prognostic impact in patients treated with allogeneic stem cell transplantation. However, the cytokine system constitutes an interacting functional network, and it may therefore be more relevant to look at serum cytokine profiles rather than the serum levels of single cytokines in allotransplanted patients. We therefore investigated the pretransplantation serum levels of 35 cytokines in a group of 44 consecutive allogeneic stem cell transplantation patients, mainly with a primary diagnosis of acute leukemia. Serum samples were collected before the start of myeloablative conditioning therapy when all patients were in complete hematologic remission. Unsupervised hierarchical clustering analysis identified three major patient groups/subsets. These groups differed especially in the levels of hepatocyte growth factor and granulocyte-colony stimulating factor, and one of the groups was characterized by low early treatment-related morbidity and high levels of hepatocyte growth factor and granulocyte-colony stimulating factor. The degree of weight gain/fluid retention after conditioning therapy did not differ between the patient subsets, but fluid retention showed a significant correlation with pretransplantation serum levels of basic fibroblast growth factor. We conclude that the pretransplantation serum cytokine profile shows a considerable variation even between patients in complete hematologic remission and is associated with clinicopathologic features.

T Cell and B Cell Immunity can be Reconstituted with Mismatched Hematopoietic Stem Cell Transplantation Without Alkylator Therapy in Artemis-Deficient Mice Using Anti-Natural Killer Cell Antibody and Photochemically Treated Sensitized Donor T Cells

2011-10-19

Children with Artemis-deficient T−B−NK+ severe combined immunodeficiency are at high risk for graft rejection from natural killer (NK) cells and toxicity from increased sensitivity to the alkylating agents used in mismatched hematopoietic stem cell transplantation (HSCT). We evaluated the use of a nonalkylating agent regimen before HSCT in Artemis-deficient (mArt−/−) C57Bl/6 (B6) mice to open marrow niches and achieve long-term multilineage engraftment with full T cell and B cell immune reconstitution. We found that partial depletion of both recipient NK cells using anti-NK1.1 monoclonal antibody and donor T cells sensitized to recipient splenocytes was necessary. BALB/c-sensitized T cells (STCs) were photochemically treated (PCT) with psoralen and UVA light to inhibit proliferation, reduce the risk of graft-versus-host disease (GVHD), and target host hematopoietic stem cells (HSCs). A dose of 4 × 105 PCT STCs coinjected with 1 × 105 lineage-depleted c-kit+ BALB/c HSCs resulted in 43.9% ± 3.3% CD4+ and 10.9% ± 1.2% CD8+ donor T cells in blood, 29% ± 7.8% and 21.7% ± 4.0 donor B220+ IgM+ in spleen and bone marrow, and 15.0% ± 3.6% donor Gran-1+ cells in bone marrow at 6 months post-HSCT versus 0.02% ± 0.01%, 0.13% ± 0.10%, 0.53% ± 0.16%, 0.49% ± 0.09%, and 0.20% ± 0.06%, respectively, in controls who did not receive PCT STCs. We found that STCs target host HSCs and that PCT STCs are detectable only up to 24 hours after infusion, in contrast to non–photochemically treated STCs, which proliferate resulting in fatal GVHD. Increased mortality in the groups receiving 4-6 × 105 PCT STCs was associated with evidence of GVHD, particularly in the recipients of 6 × 105 cells. These results demonstrate that blocking NK cell–mediated resistance and making niches in bone marrow are both essential to achieving multilineage engraftment of mismatched donor cells and T cell and B cell reconstitution, even though GVHD is not completely eliminated.

Identification of a Coordinated CD8 and CD4 T Cell Response Directed Against Mismatched HLA Class I Causing Severe Acute Graft-versus-Host Disease

2011-10-19

After HLA class I-mismatched stem cell transplantation, allo-HLA–directed CD8 T cell responses can be activated without the help of CD4 T cells if memory CD8 T cells cross-reactive against the allo-HLA class I are present or if naïve CD8 T cells are administered during inflammatory conditions. However, in the absence of inflammatory conditions, cooperation between CD4 and CD8 T cells likely is required for an effective primary CD8 T cell response directed against allo-HLA class I. In this study we investigated whether a coordinated response of CD8 and CD4 T cells could be demonstrated in an HLA class I–directed immune response in a patient who developed severe graft-versus-host disease (GVHD) after the administration HLA-A2–mismatched donor lymphocyte infusion in the absence of inflammatory conditions. A previously administered donor lymphocyte infusion from the same donor did not lead to an immune response, excluding the presence of a substantial pool of CD8 T cells cross-reactive against HLA-A2 within the memory T cell compartment of the donor. Analysis of isolated donor CD8 and CD4 T cell clones activated during the GVHD revealed a polyclonal CD8 T cell response directed against the mismatched HLA-A2 and a polyclonal CD4 T cell response recognizing HLA-A2–derived peptides presented in HLA class II. In addition, leukemic blasts present at the time of the emergence of GVHD expressed HLA-A2 and HLA class II and could activate both the CD4 and CD8 alloreactive T cells. Our results demonstrate that the GVHD was mediated by a cooperative CD4 and CD8 response directed against the mismatched HLA-A2 and suggest that leukemic blasts possibly activated this CD8 and CD4 T cell response.

Limiting the Daily Total Nucleated Cell Dose of Cryopreserved Peripheral Blood Stem Cell Products for Autologous Transplantation Improves Infusion-Related Safety with No Adverse Impact on Hematopoietic Engraftment

2011-06-16

Cryopreserved peripheral blood stem cell (PBSC) products can induce a number of infusion-related adverse reactions, including life-threatening cardiac, neurologic, and other end-organ complications. Preliminary analyses suggested limiting the daily total nucleated cell dose infused might decrease the incidence of these adverse effects. A policy change implemented in December 2007, limiting the total nucleated cell (TNC) dose to <1.63 × 109 TNC/kg/day, allowed us to assess the impact of this intervention on infusion-related safety, infusion schedules, engraftment, and costs in cohorts of patients undergoing autologous stem cell transplants (ASCTs) 2 years before (325 ASCTs in 288 patients) and 2 years after the policy change (519 ASCTs in 479 patients). The percentage of autologous transplant patients requiring multiple day infusions increased from 6% to 24%. Concurrently, the incidence of infusion-related grade 3-5 severe infusion-related adverse events (SAEs) decreased significantly, from 4% (13 of 325) prepolicy change to 0.6% (3 of 519) postpolicy change (P < .0004). Multiday infusions were not associated with increased time to neutrophil or platelet engraftment or the costs of transplantation. We conclude that limiting the daily TNC dose improved the safety of this procedure without compromising engraftment or increasing the costs of the procedure.

Effect of Early Posttransplantation Tacrolimus Concentration on the Development of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donors

2011-06-27

Only limited data are available regarding the relationship between blood concentration of tacrolimus and its efficacy in preventing acute graft-versus-host disease (aGVHD). We retrospectively evaluated the effects of the whole blood concentration of tacrolimus, which was measured by an automated microparticle enzyme immunoassay, early after allogeneic hematopoietic stem cell transplantation (HSCT) upon the development of aGVHD. Sixty patients, who underwent allogeneic HSCT from serologically human-leukocyte antigen-matched unrelated donors and received continuous infusion of tacrolimus with short-term methotrexate for GVHD prophylaxis, were included in this study. The target range of the blood concentration of tacrolimus was set at 10 to 20 ng/mL, and the level was maintained within this range in all patients. However, the mean blood concentration of tacrolimus during the third week after HSCT was significantly associated with the grades of aGVHD (17.3 ± 2.1 in patients with grades 0-I vs 15.9 ± 2.8 in II-IV and 14.8 ± 2.1 in III-IV; P < .05 and <.01, respectively). Multivariate analysis also demonstrated that higher age (≥35) of donor (odds ratio [OR] = 4.28) and lower mean blood concentrations of tacrolimus during the second (OR = 0.75; 95% confidence interval [CI]: 0.58-0.98) and third weeks (OR = 0.76; 95% CI: 0.58-0.98) after HSCT were significant risk factors for grades II-IV aGVHD (P < .05). We conclude that the early posttransplantation blood concentration of tacrolimus had a significant impact on the development of moderate-to-severe aGVHD after allogeneic HSCT from an unrelated donor.

EBMT Risk Score Predicts Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Who Have Failed a Previous Transplantation Procedure

2011-07-01

Increasing numbers of allogeneic hematopoietic stem cell transplantation (allo-SCT) are being performed for patients who have failed a previous allogeneic or autologous SCT. We investigated whether the EBMT risk score could predict outcome after a subsequent allo-SCT. We analyzed prognostic factors in 124 consecutive patients who underwent a second transplantation using an allogeneic donor at our institution. Patients with either a first autologous (N = 64) or first allogeneic (N = 60) SCT were included. Age, disease stage, time interval from diagnosis to transplantation, donor type, and donor–recipient sex combination were used to establish a score from 0 to 7 points, from which 3 groups were identified. The 5-year survival probability decreased from 51.7% for risk scores 0-3 (low, n = 25), to 29.3% for risk score 4 (intermediate, n = 42), and only 10.4% for risk scores 5-7 (high, n = 57), P = .001. We propose that the EBMT risk score can identify patients most likely to benefit from a second transplantation.

Plerixafor Added to Chemotherapy Plus G-CSF Is Safe and Allows Adequate PBSC Collection in Predicted Poor Mobilizer Patients with Multiple Myeloma or Lymphoma

2011-07-26

We evaluated the safety and efficacy of plerixafor, subsequent to disease-specific chemotherapy followed by granulocyte-colony stimulating factor (G-CSF), in 37 multiple myeloma (MM) or lymphoma patients, who were candidates for autologous stem cell transplantation (ASCT) predicted as poor mobilizers (PMs). Patients were identified as predicted PMs according to the history of a previously failed mobilization attempt or the presence of ≥1 factors predicting an unsuccessful harvest, such as advanced disease, prior extensive radiotherapy, or prolonged treatment, with stem cell poisons, advanced age, or extensive bone marrow involvement. Plerixafor (0.24 mg/kg) was administered subcutaneously for up to 3 consecutive days while continuing G-CSF for 9 to 11 hours before the planned apheresis. Plerixafor administration was safe and no significant adverse events were recorded. We observed a median 4-fold increase (range: 1.4-32) in the number of circulating CD34+ cells following plerixafor compared with baseline CD34+ cell concentration (from a median of 5 cells/μL, range: 1-32, to a median of 32 cells/μL, range: 6-201). Twenty-seven of the 37 patients (14 of 17 with MM and 13 of 20 with lymphoma) had ≥2×106 CD34+ cells/kg collected in 1-3 apheretic procedures. Of the 27 patients rescued with plerixafor, 24 (13 MM, 11 lymphoma) have been transplanted with plerixafor-mobilized peripheral blood stem cells, showing a rapid and durable hematologic recovery. Our results suggest that the addition of plerixafor to G-CSF after disease-oriented chemotherapy is safe and allows for a satisfactory harvest in order to perform a safe ASCT, in a relevant proportion of lymphoma and MM patients considered to be PMs.

Double Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study from the SFGM-TC

2011-07-11

The purpose of this paper is to describe the outcome of patients who underwent double allogeneic hematopoietic stem cell transplantation (AHSCT) with reduced-intensity conditioning regimens (RIC). Forty-five patients who received double RIC-AHSCT between 1997 and 2006 were retrospectively studied. The predominant diagnosis was acute myeloid leukemia (AML) (n = 17). Other diagnoses were aplasic anemia (AA) (n = 5), myelodysplasic disorder (n = 5), acute lymphoblastic leukemia (ALL) (n = 4), chronic myelomonocytic leukemia (CML) (n = 3), myeloma (n = 3), non-Hodgkin lymphoma (NHL) (n = 3), chronic lymphocytic leukemia (CLL) (n = 2), Hodgkin's disease (HD) (n = 2), and chronic myelomonocytic leukemia (n = 1). Main indications for RIC-AHSCT 2 were relapse (n = 25, 56%) and early (n = 8, 18%) or late (n = 12, 26%) graft failure. Median delays to reach a neutrophil count of 0.5 × 109/L and platelet counts of 50 × 109/L were significantly smaller after the second AHSCT. Among 25 patients who relapsed after RIC-AHSCT 1, 14 patients (56%) presented a response improvement after RIC-AHSCT 2. In this group, 9 patients sustained a complete response and 5 patients a partial response. Moreover, among the 20 patients who had early or late graft failure following RIC-AHSCT 1, 9 (45%) finally reached an engraftment. Disease-free survival (DFS) was significantly improved after RIC-AHSCT 2. Thirteen patients (28%) died of transplant-related mortality (TRM) at a median delay of 69 days (range: 0-451) after RIC-AHSCT 2. Double RIC-AHSCT is a feasible procedure that allows a response or engraftment not observed after RIC-AHSCT 1. The main indication is relapse. However, TRM remains high.

Idiotype Immunization Following High-Dose Therapy and Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma

2011-07-06

The treatment of low- and intermediate-grade subtypes of malignant lymphoma continues to evolve. Mantle cell lymphoma (MCL) accounts for 6% of all non-Hodgkin lymphoma (NHL) and is generally considered incurable. Although high response rates can be achieved with initial chemotherapy, median survival is only 3-4 years. Intensified consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) has been reported to improve progression-free survival (PFS), but most patients eventually relapse. Indolent lymphoma accounts for 35% of all NHL and is associated with a median survival of 9 years. Similar to MCL, it is also generally considered incurable, and the PFS also appears to be improved following HDT/ASCT. We initiated a pilot study to evaluate idiotype (Id) vaccination following HDT and ASCT for patients with MCL, indolent, and transformed NHL to evaluate the ability of Id-keyhole limpet hemocyanin (KLH) to induce immune responses, and to evaluate overall survival (OS) and PFS. We treated 15 patients: 8 with MCL, 4 with follicular lymphoma, 1 with small lymphocytic lymphoma, and 2 with transformed lymphoma. After a median follow-up of approximately 6.3 years (range: 1-9), PFS and OS at 9.05 years from time of ASCT are 59% and 52%, respectively.

Accurate Targeting of Daily Intravenous Busulfan with 8-Hour Blood Sampling in Hospitalized Adult Hematopoietic Cell Transplant Recipients

2011-07-06

Daily intravenous (i.v.) busulfan is increasingly being used in hematopoietic cell transplantation (HCT) conditioning regimens. Intravenous busulfan doses administered at the traditional frequency of every 6 hours can be targeted (TBu) to a patient-specific concentration at steady state (Css) using therapeutic drug monitoring (TDM). In this report, we describe our experiences with TDM of daily i.v. busulfan in an adult population, with the specific aims of (1) evaluating covariates associated with busulfan clearance, and (2) assessing the feasibility of TDM for outpatient administration of daily TBu with pharmacokinetic sampling over 6 hours. A retrospective pharmacokinetic analysis was conducted in 87 adults receiving daily TBu as part of cyclophosphamide followed by TBU (CY/TBU), fludarabine monophosphate (fludarabine) followed by TBU, or TBU concurrent with fludarabine conditioning. The desired Css was achieved in 85% of patients receiving daily i.v. busulfan. Busulfan clearance was not associated with sex or age, but was associated with the day of dosing and conditioning regimen (P = .0016). In patients receiving CY/TBU, no differences in clearance were found between dosing days (P > .36); however, clearance decreased significantly in patients receiving fludarabine-based regimens (P = .0016). Busulfan clearance and Css estimates from pharmacokinetic sampling over 8, 11, or 24 hours were comparable (P > .4). However, pharmacokinetic modeling of individual patient concentration-time data over 6 hours could not reliably estimate busulfan clearance or Css.

Genetic Variations in the Mycophenolate Mofetil Target Enzyme Are Associated with Acute GVHD Risk after Related and Unrelated Hematopoietic Cell Transplantation

2011-07-11

Inosine monophosphate dehydrogenase (IMPDH) is the target enzyme of mycophenolate mofetil (MMF). Single nucleotide polymorphisms (SNPs) in the IMPDH1 gene are reportedly relevant to acute rejection in renal transplant patients receiving MMF. The objective of this study was to identify the impact of IMPDH1 gene polymorphisms on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Four IMPDH1 gene SNPs (IVS7 +125 G>A, IVS8-106 G>A, exon15 1572 G>A, and 5′ flanking intron-exon region C>T) were analyzed in 240 consecutive pairs of transplant recipients and their donors. The presence of the IMPDH1 IVS8−106 G/G genotype in recipients was associated with a significantly higher incidence of acute graft-versus-host disease (aGVHD) than other genotypes, in both unrelated and sibling transplantation cohorts (unrelated cohort: 83.3% vs 63.9%, P = .048; sibling cohort: 47.6% vs 17.3%, P = .008). Multivariate analysis confirmed that recipients with the IVS8−106 G/G genotype were at significantly higher risk of developing aGVHD (relative risk [RR] = 2.018, 95% confidence interval [CI]: 1.354-3.009, P = .001) and grades II-IV aGVHD (RR = 2.232, 95% CI: 1.352-3.685, P = .002). There was no association among IVS7 +125, exon15 1572, and 5′ flanking intron-exon region genotypes and the risk of aGVHD. These results represent the first report of an association between IMPDH1 gene polymorphisms and the risk of aGVHD in allo-HSCT.

Classifying Cytogenetics in Patients with Acute Myelogenous Leukemia in Complete Remission Undergoing Allogeneic Transplantation: A Center for International Blood and Marrow Transplant Research Study

2011-08-02

Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.

Reduced-Intensity Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation in Patients Over 60 Years: A Report from the SFGM-TC

2011-07-21

This retrospective multicenter report assessed the outcome of 600 patients with hematologic diseases older than 60 years who received reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT), with the specific aim to compare outcomes of patients between 60 and 65 years old (N = 493) with those older than 65 years (N = 107). Except for donor age, there were no significant differences between the groups regarding patients, diseases, and allo-HSCT characteristics. At time of RIC allo-HSCT, 276 patients (46%) were in complete remission. With a median follow-up of 22.8 and 23.7 months in the younger and the older groups, respectively, 2-year relapse, nonrelapse mortality, disease-free survival, and overall survival rates were similar in both groups (29.6% vs. 20.4%; 29.9% vs. 34.6%; 40.6% vs. 46.7%; 49.2% vs. 50.2%, respectively; P = NS for all comparisons). In a Cox multivariate analysis, after adjustment for disease and transplant factors, age per se was not an adverse factor for survival (relative risk = 1.08; 95% confidence interval, 0.81-1.44, P = .62). We conclude that in selected patients, RIC allo-HSCT could be offered to patients over 65 years old.

Development and Validation of a Test Dose Strategy for Once-Daily i.v. Busulfan: Importance of Fixed Infusion Rate Dosing

2011-07-28

Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 μM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m2 × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day −5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day −7. In the first 2 schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day −5 AUC (AUC−5) showed a high linear correlation (r2 = 0.74) to the actual AUC−5. The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500 μM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy.

Allogeneic Hematopoietic Cell Transplantation for Chronic Myelofibrosis in Australia and New Zealand: Older Recipients Receiving Myeloablative Conditioning at Increased Mortality Risk

2011-05-12

This retrospective registry analysis examined predictive factors for outcome in 57 patients who underwent allogeneic or syngeneic hematopoietic cell transplantation (HCT) for chronic myelofibrosis (CM), either primary (n = 49) or following an antecedent condition (n = 8), reported to the Australasian Bone Marrow Transplant Registry (ABMTRR) between 1993 and 2005. During the 6 years 2000 to 2005, 40 HCTs were performed for CM compared with 17 in the 7 years 1993 to 1999. Twenty-four recipients (42%) were age 50 or over at transplantation; all of these patients were transplanted after 1997, and 15 were given reduced intensity conditioning (RIC) pretransplantation. The cumulative incidence of transplantation-related mortality was 18% at 100 days and 25% at 1 year posttransplantation. Up to 1 year posttransplantation 16 patients died, with the most common causes being infection (n = 6) and graft-versus-host disease (GVHD) (n = 5). A total of 27 patients survived for 3 years or longer posttransplantation. None of these patients required regular red blood cell transfusions, and of the 17 who had not had splenectomies, none had detectable splenomegaly. Twelve patients had no detectable bone marrow fibrosis, 7 had grade 1 fibrosis, and in 8 patients no information was available. The overall survival (OS) probability for all patients was 72% at 1 year and 58% at 5 years posttransplantation. Patients age 50 and over who received myeloablative conditioning fared poorly, with 1-year overall actuarial survival of 44% compared with 77% for all other patients (P = .007). In multivariate analysis, age 50 years and over at transplantation was the only significant independent unfavorable risk factor for survival post-HCT (hazard ratio 2.71, 95% confidence interval 1.16-6.34, P = .02). This study shows a clear increase in annual numbers of allogeneic HCT performed for CM in Australia and New Zealand in recent years. Five-year survival was favorable compared with international studies, but for older recipients who received myeloablative conditioning, mortality risk was elevated.

Stable Long-Term Pulmonary Function after Myeloablative Double Cord Blood Transplant

2011-08-16

Pulmonary dysfunction has been well described after myeloablative transplantation with conventional allogeneic donors; however, whether the risk is similar after alternative donor transplantation with cord blood as the stem cell source has not yet been investigated. We performed a retrospective analysis of patients who underwent double cord blood transplantation after myeloablative conditioning. Pulmonary function tests were performed pretransplantation and at day 80, 1 year, and 2 years posttransplantation, with 56 patients included in the final analysis. No significant change from baseline with respect to the mean values and mean change in pulmonary function test values were observed at 1 year posttransplantation. The rate of lung function decline from baseline to 1 year posttransplantation was <5% in 75% patients; mildly abnormal lung function was reported in 58% of the patients. The cumulative incidence of noninfectious pulmonary complications was 9.7%. Future prospective studies are needed to confirm these findings.

Plerixafor for Autologous Peripheral Blood Stem Cell Mobilization in Patients Previously Treated with Fludarabine or Lenalidomide

2011-10-14

Fludarabine and lenalidomide are essential drugs in the front-line treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. In the European compassionate use program, 48 patients (median age 57 years) previously treated with fludarabine (median 5 cycles; range: 1-7 cycles) were given plerixafor plus granulocyte colony-stimulating factor (G-CSF) for remobilization following a primary mobilization attempt. The overall median number of CD34+ cells collected was 2.3 × 106/kg (range: 0.3-13.4). The minimum required number of CD34+ cells (≥2.0 × 106/kg) was collected from 58% of patients in a median of 2 days. Thirty-five patients (median age = 57 years) previously treated with lenalidomide (median 5 cycles; range: 1-10 cycles) were given plerixafor plus G-CSF for remobilization. The overall median number of CD34+ cells collected was 3.4 × 106/kg (range: 1.1-14.8). The minimum required number of CD34+ cells (≥2.0 × 106 per kg) was collected from 69% of patients in a median of 2 days. In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for novel mobilization regimens algorithms in this subgroup of patients.

Dasatinib as Salvage Therapy for Steroid Refractory and Imatinib Resistant or Intolerant Sclerotic Chronic Graft-versus-Host Disease

2011-11-07

Sclerotic chronic graft-versus-host disease (scGVHD) is a severe form of this disease that resembles systemic sclerosis and has limited and disappointing treatment options. Tyrosine kinase inhibitors (TKI) targeting up-regulated profibrotic pathways, such as imatinib mesylate, have been proposed as a potential therapeutic approach for patients with scGVHD. Dasatinib, a second-generation TKI with a well-established safety and efficacy profile in chronic myeloid leukemia patients, who are refractory or intolerant to imatinib, has also shown potent antifibrotic effects. We present here the first direct clinical evidence, from 3 patients treated in a small single-center series, suggesting that dasatinib can be a therapeutic option for patients with severe scGVHD resistant or intolerant to imatinib. All patients achieved partial response, with improvement in scGHVD target organs severity, joint mobility, lung impairment, and deep fibrotic lesions. This clinical response has remained stable or continued to improve after a median of 22 months (20-25) on dasatinib treatment, with very good tolerance. In addition, corticosteroids could be discontinued or significantly reduced in all patients. This clinical evidence suggests that dasatinib could be a safe and effective alternative for scGVHD patients refractory to corticosteroids and resistant or intolerant to imatinib. Based on these preliminary findings, and in order to address appropriate patient selection, time of intervention, and choice of drug, future larger studies should more formally establish the efficacy and safety of second-generation TKI for the treatment of scGVHD.

A Phase I Study of Gemtuzumab Ozogamicin (GO) in Combination with Busulfan and Cyclophosphamide (Bu/Cy) and Allogeneic Stem Cell Transplantation in Children with Poor-Risk CD33+ AML: A New Targeted Immunochemotherapy Myeloablative Conditioning (MAC) Regimen

2011-11-10

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day −14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m2, busulfan on days −7, −6, −5, −4 (12.8-16.0 mg/kg), and cyclophosphamide on days −3 and −2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m2. No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m2 in combination with Bu/Cy is currently being tested in a phase II study.

2012 BMT Tandem Meetings

2011-12-16

2012 BMT TANDEM MEETINGS WILL BE FEB. 1-5 IN SAN DIEGO The combined 2012 annual meetings of ASBMT and the Center for International Blood and Marrow Transplant Research (CIBMTR) will be Feb. 1-5 at the Manchester Grand Hyatt in San Diego.

Purpose and Scope

2012-02-01

Editorial Board

2012-02-01

Officers and Directors of ASBMT

2012-02-01

Biology of Blood and Marrow Transplantation

New Hope for Mobilization Failures . . . Again

My AML Cytogenetics Classification Scheme Is Better Than Yours

NCI, NHLBI/PBMTC First International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Health-Related Quality of Life, Functional, and Neurocognitive Outcomes

The National Marrow Donor Program’s Symposium on Hematopoietic Cell Transplantation in 2020: A Health Care Resource and Infrastructure Assessment

Easy-to-Read Informed Consent Forms for Hematopoietic Cell Transplantation Clinical Trials

The Pretransplantation Serum Cytokine Profile in Allogeneic Stem Cell Recipients Differs from Healthy Individuals, and Various Profiles are Associated with Different Risks of Posttransplantation Complications

T Cell and B Cell Immunity can be Reconstituted with Mismatched Hematopoietic Stem Cell Transplantation Without Alkylator Therapy in Artemis-Deficient Mice Using Anti-Natural Killer Cell Antibody and Photochemically Treated Sensitized Donor T Cells

Identification of a Coordinated CD8 and CD4 T Cell Response Directed Against Mismatched HLA Class I Causing Severe Acute Graft-versus-Host Disease

Limiting the Daily Total Nucleated Cell Dose of Cryopreserved Peripheral Blood Stem Cell Products for Autologous Transplantation Improves Infusion-Related Safety with No Adverse Impact on Hematopoietic Engraftment

Effect of Early Posttransplantation Tacrolimus Concentration on the Development of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donors

EBMT Risk Score Predicts Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Who Have Failed a Previous Transplantation Procedure

Plerixafor Added to Chemotherapy Plus G-CSF Is Safe and Allows Adequate PBSC Collection in Predicted Poor Mobilizer Patients with Multiple Myeloma or Lymphoma

Double Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study from the SFGM-TC

Idiotype Immunization Following High-Dose Therapy and Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma

Accurate Targeting of Daily Intravenous Busulfan with 8-Hour Blood Sampling in Hospitalized Adult Hematopoietic Cell Transplant Recipients

Genetic Variations in the Mycophenolate Mofetil Target Enzyme Are Associated with Acute GVHD Risk after Related and Unrelated Hematopoietic Cell Transplantation

Classifying Cytogenetics in Patients with Acute Myelogenous Leukemia in Complete Remission Undergoing Allogeneic Transplantation: A Center for International Blood and Marrow Transplant Research Study

Reduced-Intensity Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation in Patients Over 60 Years: A Report from the SFGM-TC

Development and Validation of a Test Dose Strategy for Once-Daily i.v. Busulfan: Importance of Fixed Infusion Rate Dosing

Allogeneic Hematopoietic Cell Transplantation for Chronic Myelofibrosis in Australia and New Zealand: Older Recipients Receiving Myeloablative Conditioning at Increased Mortality Risk

Stable Long-Term Pulmonary Function after Myeloablative Double Cord Blood Transplant

Plerixafor for Autologous Peripheral Blood Stem Cell Mobilization in Patients Previously Treated with Fludarabine or Lenalidomide

Dasatinib as Salvage Therapy for Steroid Refractory and Imatinib Resistant or Intolerant Sclerotic Chronic Graft-versus-Host Disease

A Phase I Study of Gemtuzumab Ozogamicin (GO) in Combination with Busulfan and Cyclophosphamide (Bu/Cy) and Allogeneic Stem Cell Transplantation in Children with Poor-Risk CD33+ AML: A New Targeted Immunochemotherapy Myeloablative Conditioning (MAC) Regimen

2012 BMT Tandem Meetings

Purpose and Scope

Editorial Board

Officers and Directors of ASBMT

Contents