Paul J. Shaughnessy

First and Second-Line Systemic Treatment of Acute Graft-versus-host Disease: Recommendations of the American Society of Blood and Marrow Transplantation

Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of aGVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of aGVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of aGVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Because the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous results and the design of future studies.

Optimizing Autologous Stem Cell Mobilization Strategies to Improve Patient Outcomes: Consensus Guidelines and Recommendations

Autologous hematopoietic stem cell transplantation (aHSCT) is a well-established treatment for malignancies such as multiple myeloma (MM) and lymphomas. Various changes in the field over the past decade, including the frequent use of tandem aHSCT in MM, the advent of novel therapies for the treatment of MM and lymphoma, and the addition of new stem cell mobilization techniques, have led to the need to reassess current stem cell mobilization strategies. Mobilization failures with traditional strategies are common and result in delays in treatment and increased cost and resource utilization. Recently, plerixafor-containing strategies have been shown to significantly reduce mobilization failure rates, but the ideal method to maximize stem cell yields and minimize costs associated with collection has not yet been determined. A panel of experts convened to discuss the currently available data on autologous hematopoietic stem cell mobilization and transplantation and to devise guidelines to optimize mobilization strategies. Herein is a summary of their discussion and consensus.

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

We conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.

Cost and Clinical Analysis of Autologous Hematopoietic Stem Cell Mobilization with G-CSF and Plerixafor Compared to G-CSF and Cyclophosphamide

Plerixafor plus granulocyte-colony stimulating factor (G-CSF) has been shown to mobilize more CD34(+) cells than G-CSF alone for autologous hematopoietic stem cell transplantation (HSCT). However, many centers use chemotherapy followed by G-CSF to mobilize CD34(+) cells prior to HSCT. We performed a retrospective study of patients who participated in the expanded access program (EAP) of plerixafor and G-CSF for initial mobilization of CD34(+) cells, and compared outcomes to matched historic controls mobilized with cyclophosphamide 3-5 g/m(2) and G-CSF at 2 centers that participated in the EAP Control patients were matched for age, sex, disease, disease stage, and number of prior therapies. Mobilization costs were defined to be the costs of medical procedures, resource utilization, and medications. Median national CMS reimbursement rates were used to establish the costs of procedures, hospitalization, provider visits, apheresis, CD34(+) cell processing and cryopreservation. Average sale price was used for G-CSF, plerixafor, cyclophosphamide, MESNA, antiemetics, and antimicrobials. A total of 33 patients from the EAP and 33 matched controls were studied. Two patients in the control group were hospitalized for neutropenic fever during the mobilization period. Apheresis started on the scheduled day in 33 (100%) study patients and in 29 (88%) control patients (P = 0.04). Sixteen (48%) control patients required weekend apheresis. There was no difference in number of CD34(+) cells collected between the groups, and all patients proceeded to HSCT with no difference in engraftment outcomes. Median total cost of mobilization was not different between the plerixafor/G-CSF and control groups (

Peripheral Blood Progenitor Cell Mobilization for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation

14,224 versus

Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from the American Society for Blood and Marrow Transplantation.

18,824; P = .45). In conclusion, plerixafor/G-CSF and cyclophosphamide/G-CSF for upfront mobilization of CD34(-) cells resulted in similar numbers of cells collected, costs of mobilization, and clinical outcomes. Additionally, plerixafor/G-CSF mobilization resulted in more predictable days of collection, no weekend apheresis procedures, and no unscheduled hospital admissions.

Expression of Adhesion Molecules on CD34 + Cells in Peripheral Blood of Non-Hodgkin's Lymphoma Patients Mobilized with Different Growth Factors

Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.

Extracorporeal Photopheresis for the Prevention of Acute GVHD in Patients Undergoing Standard Myeloablative Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation

Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. Thus, the role of hematopoietic stem cell transplantation (HCT) must be considered in the context of this evolution. In this evidence-based review, we have critically analyzed the data from the most recent clinical trials to better understand how to incorporate HCT and when HCT is indicated. We have provided our recommendations based on strength of evidence with the knowledge that ongoing clinical trials make this a dynamic field. Within this document, we discuss the decision to proceed with autologous HCT, factors to consider before proceeding to HCT, the role of tandem autologous HCT, post-HCT maintenance therapy, and the role of allogeneic HCT for patients with MM.

Mobilization of dendritic cells and NK cells in non-Hodgkin's lymphoma patients mobilized with different growth factors.

Adhesion molecules on CD34+ cells were implicated in the process of peripheral blood stem cell (PBSC) mobilization and homing. We studied the mobilization of CD34+Thy1+ cells, CD34+ very late‐acting antigen (VLA)4+ cells, and CD34+L‐selectin+ cells in non‐Hodgkins lymphoma patients mobilized with cyclophosphamide plus G‐CSF, GM‐CSF, or GM‐CSF followed by G‐CSF. The mean percentage of CD34+ cells in the bone marrow (BM) expressing Thy1 was 23.6% ± 11% and 17.8% ± 8% in the PB before mobilization, and was markedly decreased to 4.5% ± 3.3% in the apheresis collections. Similarly, the mean percentage of CD34+ cells expressing L‐selectin was 35.8% ± 4.3% in the BM, 21.6% ± 4.1% in the PB before mobilization and was markedly decreased to 9.1% ± 2.5% in the apheresis collections. Patients in the three arms of the study had a similar pattern of CD34+Thy1+ and CD34+L‐selectin+ cell mobilization. Also, a similar pattern of coexpression of CD34+Thy1+ and CD34+L‐selectin+ cells was observed when the patients were regrouped as “good mobilizers” (≥2 × 106 CD34+CD45dim cells/kg, in four collections) and “poor mobilizers” (<0.4 × 106 CD34+CD45dim cells/kg, in two collections).

Conditioning Chemotherapy Dose Adjustment in Obese Patients: A Review and Position Statement by the American Society for Blood and Marrow Transplantation Practice Guideline Committee

GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II–IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78–94%) and 77% (95% CI, 64–86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II–IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24–0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.