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• Allogeneic hematopoietic cell transplantation in patients 60 to 70 years of age with de novo high-risk MDS or secondary AML - a comparison with patients lacking donors who received azacitidine.

  Authors: Uwe Platzbecker, Johannes Schetelig, Jürgen Finke, Rudolf Trenschel, Bart L Scott, Guido Kobbe, Kerstin Schaefer-Eckart, Martin Bornhäuser, Raphael Itzykson, Ulrich Germing, Dietrich Beelen, Gerhard Ehninger, Pierre Fenaux, H-Joachim Deeg, Lionel Adès

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Standard first-line therapy for older patients with high-risk MDS consists of hypomethylating agents such as azacitidine (AZA). However, the only approach with curative potential remains allogeneicStandard first-line therapy for older patients with high-risk MDS consists of hypomethylating agents such as azacitidine (AZA). However, the only approach with curative potential remains allogeneic hematopoietic cell transplantation (HCT). So far no direct comparison of both strategies has been carried out. The outcomes of two well balanced cohorts of high-risk MDS patients defined by age (60-70 years), performance status (ECOG ≤2) and donor availability (yes/no) were compared including 103 patients undergoing HCT and 75 patients without this option who received AZA. The estimated 2-year overall survival (OS) after the start of treatment was 39% (95% CI, 30% to 50%) for the HCT patients and 23% (95% CI, 14 to 40%) for the AZA patients. In a multivariate Cox regression analysis of all (n=178) patients ECOG score (0 vs. 1 vs. 2, HR: 2.9/3.9, p<0.001), cytogenetics (good vs. intermediate vs. poor, HR: 1.2/1.7, p=0.026) and type of treatment (HCT vs. AZA, HR: 0.3, p=0.007) were associated with OS. This retrospective cohort analysis suggests a survival advantage with allogeneic HCT compared to treatment with AZA in medically fit high-risk MDS patients 60 to 70 years of age, Prospective controlled studies are warranted.

• Histological assessment of the sclerotic Graft-versus-Host response in the humanized RAG2-/-γc-/- mouse model.

  Authors: Marieke C H Hogenes, Suzanne van Dorp, Joyce van Kuik, Filipa R P Monteiro, Natalie Ter Hoeve, Marijke R van Dijk, Anton C Martens, Roel A de Weger

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Graft versus Host disease (GvHD) still remains a frequently occurring and difficult to treat complication in human allogeneic stem cell transplantation. Murine transplantation models are often usedGraft versus Host disease (GvHD) still remains a frequently occurring and difficult to treat complication in human allogeneic stem cell transplantation. Murine transplantation models are often used to study and understand the complex pathogenesis of GvHD and to explore new treatment-strategies. Although GvHD-kinetics in murine models may differ from the human counterpart, for identification of the crucial factors responsible for the major pathology in GvHD adequate models are essential. In this report we present a detailed description of the specific histological features of a Graft versus Host induced fibrotic response in xenogeneic RAG2(-/-)γc(-/-) mice, after total body irradiation and injection with human peripheral blood mononuclear cells (huPBMC's). We describe the full morphological feature of this reaction, including a detailed analysis of the specific tissue infiltration patterns of the huPBMC's. Our data show the development of fibrosis, predominantly near blood vessels, and reveals different cell-populations and specific cell-migration patterns in the affected organs. The combination of immunohistochemical cell characterization and mRNA expression analysis of both human (donor) and murine (host) derived cytokines reveal an interaction between host tissues and donor derived cells in an entangled cytokine profile, in which both donor- and host derived cytokines contribute to the formation of fibrosis.

• Armed killers face off against Cytomegalovirus.

  Authors: Maxim Norkin, John R Wingard

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

• Cord-blood hematopoietic stem-cell transplantation confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis.

  Authors: Joshua A Hill, Sophia Koo, Belisa B Guzman Suarez, Vincent T Ho, Corey Cutler, John Koreth, Philippe Armand, Edwin P Alyea, Lindsey R Baden, Joseph H Antin, Robert J Soiffer, Francisco M Marty

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem-cell transplantation (HSCT); its most severe manifestation is the syndrome of post-transplantation acute limbicHuman herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem-cell transplantation (HSCT); its most severe manifestation is the syndrome of post-transplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1,344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1,243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in CSF specimens in addition to symptoms and studies indicating limbic encephalitis. 19 (1.4%) cases of HHV6-PALE were identified during this study; 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (p<0.001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio (aHR) 20.0; 95% confidence interval (CI), 7.3-55.0; p<0.001), time-dependent acute graft-versus-host disease grades II-IV (aHR 7.5; 95% CI, 2.8-19.8; p<0.001), and adult-mismatched donor (aHR 4.3; 95% CI, 1.1-17.3; p=0.04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV6-PALE and greater morbidity from this disease.

• Safety of Posaconazole and Sirolimus Co-administration in Allogeneic Hematopoietic Stem-Cell Transplantation.

  Authors: David W Kubiak, Sophia Koo, Sarah P Hammond, Philippe Armand, Lindsey R Baden, Joseph H Antin, Francisco M Marty

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  BACKGROUND: Sirolimus is used in allogeneic hematopoietic stem-cell transplantation (HSCT) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this populationBACKGROUND: Sirolimus is used in allogeneic hematopoietic stem-cell transplantation (HSCT) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Co-administration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. METHODS: We identified 15 HSCT patients at our institution receiving a steady state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. RESULTS: All patients underwent HSCT for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve (80%) patients received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (IQR 25, 177; range 6, 503). The median daily dose of sirolimus (2 mg/day) prior to initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during co-administration, but only one patient experienced an adverse event potentially associated with sirolimus exposure during the first month of co-administration. This patient's sirolimus dose was empirically reduced by only 30% on posaconazole initiation. CONCLUSIONS: Concurrent sirolimus and posaconazole use appears to be well tolerated with a 33-50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation.

• Fludarabine-based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose De-escalation Study Show Life-Threatening Adverse Events at Pre-Defined Cyclophosphamide Dose Levels.

  Authors: Jakub Tolar, H Joachim Deeg, Sally Arai, Mitchell Horwitz, Joseph H Antin, John McCarty, Roberta Adams, Marian Ewell, Eric Leifer, Iris Gersten, Shelly Carter, Mary M Horowitz, Ryotaro Nakamura, Michael A Pulsipher, Nancy L Difronzo, Dennis Confer, Mary Eapen, Paolo Anderlini

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose de-escalation in a fludarabine (FLU)-based conditioning regimen for marrow transplantation from unrelatedExcessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose de-escalation in a fludarabine (FLU)-based conditioning regimen for marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin (ATG), FLU, and low-dose total body irradiation (TBI). The starting CY dose was 150 mg/kg with de-escalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excess organ toxicity (n=6) or viral pneumonia (n=1) resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with TBI (2 Gy), FLU (120 mg/m(2)), and ATG was associated with excessive organ toxicity.

• Phase I study of the tolerability and pharmacokinetics of palifermin in children undergoing allogeneic hematopoietic stem cell transplantation.

  Authors: Ashok Srinivasan, Kimberly A Kasow, Shane Cross, Melissa Parrish, Chong Wang, Deo K Srivastava, Xiangjun Cai, John C Panetta, Wing Leung

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  The maximum tolerated dose of palifermin, a keratinocyte growth factor, in children is not known, and its pharmacokinetics in this population has not been well studied. This phase I study ofThe maximum tolerated dose of palifermin, a keratinocyte growth factor, in children is not known, and its pharmacokinetics in this population has not been well studied. This phase I study of palifermin was designed to evaluate its tolerability at doses of 40, 60 and 90 μg/kg/day, in children 2-18 years of age, receiving a myeloablative preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). Palifermin in each cohort was given for 3 consecutive days prior to the preparative regimen, and for 3 days after the stem cell infusion. Twelve patients were enrolled. Palifermin at a dose of 90 μg/kg/day was tolerated in 6 patients without a dose-limiting toxicity. All patients had at least one adverse event, mostly NCI grade 1 or 2 in severity. Skin rash, NCI grade 2 or lower, was the most common adverse event seen in 67% of patients. Only 3 patients (25%) had mucositis. The area under the concentration-time curve increased proportional to the dose, and approximately 97% of palifermin exposure occurred in the first 24 hours after dosing. Palifermin clearance was observed to increase linearly with body weight supporting dosing by body weight. The mean clearance was 1893 mL/hour/kg, and it did not change significantly between administration of the first and last dose (p=0.8). The mean elimination half-life was 4.6 hours. Palifermin was tolerated at a dose of 90 μg/kg/day, and exhibits linear pharmacokinetics in children undergoing allogeneic HSCT.

• Tandem Transplantation for Follicular Lymphoma: The best of both worlds?

  Authors: Ginna G Laport

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

• Human Parainfluenza Virus Infection following Hematopoietic Stem Cell Transplantation: Risk Factors, Management, Mortality, and Changes over Time.

  Authors: Celalettin Ustun, Jiří Slabý, Ryan M Shanley, Jan Vydra, Angela R Smith, John E Wagner, Daniel J Weisdorf, Jo-Anne H Young

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Human parainfluenza viruses (HPIV) are uncommon, yet high-risk pathogens after hematopoietic stem cell transplantation (HCT). We evaluated 5178 pediatric and adult patients undergoing HCT betweenHuman parainfluenza viruses (HPIV) are uncommon, yet high-risk pathogens after hematopoietic stem cell transplantation (HCT). We evaluated 5178 pediatric and adult patients undergoing HCT between 1974 and 2010 to determine the incidence, risk factors, response to treatment, and outcome of HPIV infection as well as any change in frequency or character of HPIV infection over time. HPIV was identified in 173 patients (3.3%); type 3 was most common (66%). HPIV involved the upper respiratory tract (URTI) (57%), lower respiratory tract (LRTI) (9%), and both (34%) areas of the respiratory tract, at a median of 62 days after transplant. In more recent years, HPIV has occurred later after HCT, while the proportion with nosocomial infection and mortality decreased. Over the last decade, HPIV was more common in older patients and in those receiving reduced intensity conditioning (RIC). RIC was a significant risk factor for later (beyond day +30) HPIV infections and this association was strongest in patients with URTI. HCT using a matched unrelated donor (MUD), mismatched related donor (MMRD), age 10-19 years, and graft-versus-host disease (GVHD) were all risk factors for HPIV infections. LRTI, early (<30 days) infections, age 10-19 years, MMRD, steroid use, and coinfection with other pathogens were risk factors for mortality. The survival of patients with LRTI, especially very early infections, was poor regardless of ribavirin treatment. HPIV incidence remains low, but may have delayed onset associated with RIC regimens and improving survival. Effective prophylaxis and treatment for HPIV are needed.

• Incidence, Risk Factors for Early Hepatotoxicity and its Impact on Survival in Patients with Myelofibrosis Undergoing Allogeneic Hematopoietic Cell Transplantation.

  Authors: Kit Man Wong, Eshetu G Atenafu, Dennis Kim, John Kuruvilla, Jeffrey H Lipton, Hans Messner, Vikas Gupta

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Allogeneic hematopoietic cell transplantation (HCT) is commonly associated with hepatic complications. Patients with myelofibrosis (MF) often develop liver dysfunction in the early post-transplantAllogeneic hematopoietic cell transplantation (HCT) is commonly associated with hepatic complications. Patients with myelofibrosis (MF) often develop liver dysfunction in the early post-transplant period, but this has not been studied in a systematic fashion. We retrospectively evaluated 53 patients with MF who underwent HCT to assess the incidence of acute liver toxicity, risk factors and its impact on survival. A comparison for acute hepatic complications was made with a matched control of 53 patients with myelodysplastic syndrome (MDS). In the first 6 weeks after HCT, the incidence of mild (34.2 to 102.6μM), moderate (102.6 to 342μM) and severe (>342μM) hyperbilirubinemia in MF was 34%, 40% and 4%, respectively (normal <22μM). Transaminitis was mild/moderate (2-10x ULN) in 23% and severe (>10x ULN) in 6% of MF patients. Veno-occlusive disease (VOD) as defined by the Baltimore criteria was observed in 19 (36%) patients with MF. In comparison to MDS, MF was associated with a significantly higher incidence of moderate/severe hyperbilirubinemia (44% vs. 21%, p=0.02) and VOD (36% vs. 19%, p=0.05). A history of portal hypertension, biopsy proven hepatic iron overload or splanchnic vein thrombosis was a strong predictor of moderate/severe hyperbilirubinemia (p=0.02). Acute hepatocellular injury with moderate/severe hyperbilirubinemia or transaminitis was associated with inferior survival at 12 months (p=0.02) in MF. We conclude that patients with MF are at significant risk of early hepatotoxicity after HCT, which is associated with an adverse impact on survival.

• American Society of Blood and Marrow Transplantation: Guidelines for Training in Hematopoietic Progenitor Cell Transplantation.

  Authors: Shakila Khan, Mark B Juckett, Krishna V Komanduri, Amrita Krishnan, Linda J Burns

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Advances in hematopoietic progenitor cell transplantation (HCT) have led to an increasing number of transplants being performed and a concomitant requirement for physicians skilled in transplantAdvances in hematopoietic progenitor cell transplantation (HCT) have led to an increasing number of transplants being performed and a concomitant requirement for physicians skilled in transplant care. Guidelines for training transplant physicians were published in 2001. However, over the past decade there has been a rapid expansion of the medical knowledge and skill set required of transplant physicians in order for them to deliver the highest quality of care. Recognizing the importance of education for transplant programs, the American Society of Blood and Marrow Transplant established a Committee on Education in 2010. The updated guidelines presented here by the Committee provide an extensive and detailed framework for use by HCT educators and directors in developing HCT training programs and evaluating and mentoring their trainees.

• Selective purging of human multiple myeloma cells from autologous stem cell transplant grafts using oncolytic myxoma virus.

  Authors: Eric Bartee, Winnie S Chan, Jan S Moreb, Christopher R Cogle, Grant McFadden

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Autologous stem cell transplantation (ASCT) and novel therapies have improved overall survival of patients with multiple myeloma; however, most patients relapse and eventually succumb to theirAutologous stem cell transplantation (ASCT) and novel therapies have improved overall survival of patients with multiple myeloma; however, most patients relapse and eventually succumb to their disease. Evidence indicates that residual cancer cells contaminate autologous grafts and may contribute to early relapses after ASCT. Here, we demonstrate that ex vivo treatment with an oncolytic poxvirus called myxoma virus results in specific elimination of human myeloma cells by inducing rapid cellular apoptosis while fully sparing normal hematopoietic stem and progenitor cells (HSPCs). The specificity of this elimination is based on strong binding of the virus to myeloma cells coupled with an inability of the virus to bind or infect CD34(+) HSPCs. These two features allow myxoma to readily identify and distinguish even low levels of myeloma cells in complex mixtures. This ex vivo MYXV treatment also effectively inhibits systemic in vivo engraftment of human myeloma cells into immunodeficient mice and results in efficient elimination of primary CD138(+) myeloma cells contaminating patient hematopoietic cell products. We conclude that ex vivo myxoma treatment represents a safe and effective method to selectively eliminate myeloma cells from hematopoietic autografts prior to reinfusion.

• The Comparison of Allogeneic Stem Cell Transplantation from Family-mismatched/haploidentical Donors with Unrelated Donors in Adults with High-risk Acute Myeloid Leukemia.

  Authors: Byung-Sik Cho, Jae-Ho Yoon, Seung-Hwan Shin, Seung-Ah Yahng, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min, Chong-Won Park, Hee-Je Kim

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  To weigh the pros and cons of familial-mismatched/haploidentical transplantation (FMT) in high-risk acute myeloid leukemia, we assessed outcomes of 23 patients who underwent FMT, usingTo weigh the pros and cons of familial-mismatched/haploidentical transplantation (FMT) in high-risk acute myeloid leukemia, we assessed outcomes of 23 patients who underwent FMT, using reduced-intensity conditioning with TBI 800 cGy/busulfan/fludarabine/antithymocyte globulin without ex vivo T-cell depletion, compared to 33 and 13 patients who underwent well-matched unrelated donor transplantation (WM-UDT) and partially-matched unrelated donor transplantation (PM-UDT), respectively, during the same period. FMT not only had a similar pattern of engraftment and immune reconstitution, but also comparable incidences and severity of acute and chronic graft-versus-host disease with WM-UDT and PM-UDT. Patients of FMT did not experience any form of engraftment failure. However, the cumulative incidence of CMV DNAemia in FMT was significantly higher than in unrelated donors (P=0.036). After a median follow-up of 28 months, overall survival, disease-free survival, relapse, and non-relapse mortality were 83%, 74%, 20%, and 7% for WM-UDT, 51%, 51%, 31%, and 18% for PM-UDT, and 66%, 64%, 26%, and 10% for FMT, respectively, showing a trend for favorable survival outcomes of WM-UDT over FMT, and FMT over PM-UDT. However, we did not find significant statistical differences in survival according to donor types, which needs to be interpreted with caution because of limited power calculations due to the small number of each donor group. This pilot study suggests the feasibility of FMT using our novel regimen with careful evaluation of CMV DNAemia, compared to WM-UDT and PM-UDT. Further trials with a large number of patients, comparing FMT directly with other donor types, are needed.

• Extensive Dental Caries in Patients with Oral Chronic Graft-versus-Host Disease.

  Authors: Paolo Castellarin, Kristen Stevenson, Matteo Biasotto, Anna Yuan, Sook-Bin Woo, Nathaniel Simon Treister

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  OBJECTIVE: The oral cavity is one of the most frequently affected sites by cGVHD following allogeneic hematopoietic cell transplantation (alloHCT), and can be a significant source of patientOBJECTIVE: The oral cavity is one of the most frequently affected sites by cGVHD following allogeneic hematopoietic cell transplantation (alloHCT), and can be a significant source of patient morbidity due to both mucosal and salivary gland involvement. The development of dental decay is a potentially devastating oral complication that has only rarely been reported in the transplantation literature. The purpose of this study was to comprehensively characterize a cohort of patients with cGVHD that subsequently developed extensive dental caries. METHODS: A retrospective case-record review was conducted for patients who had undergone alloHCT at Dana-Farber/Brigham and Women's Cancer Center between 1990 and 2010 and developed cGVHD-associated rampant dental decay. All patients underwent dental evaluations before and after alloHCT that consisted of a soft and hard tissue examination and dental radiographs. Caries diagnosed from the pre-alloHCT evaluation were treated definitively such that all patients were considered free of caries at the time of admission for HCT. RESULTS: A total of 21 patients were identified with a median time of cGVHD onset of 5.4 months (range 2.2-18.5) post-alloHCT. All patients were diagnosed with oral cGVHD, with 90% demonstrating mucosal involvement, and 95% with salivary gland involvement. Post-alloHCT dental evaluation was performed at a median of 22 months (range 4-81) after alloHCT. when ten patients were diagnosed with gross caries and eight patients presented four or more affected teeth. Cervical and interproximal patterns of dental caries were frequently diagnosed. The proportion of patients with gross, one surface, and greater than one surface caries, categorized as 0, 1-3, or ≥4, were significantly higher post-alloHCT compared to pre-alloHCT with at least 50% of patients experiencing an increase. CONCLUSIONS: Patients with oral cGVHD, who were free of caries at the time of transplantation, developed extensive areas of cervical decay in a median time of less than two years post-alloHCT. This is the first comprehensive characterization of this severe late complication of alloHCT and oral cGVHD. Greater awareness on the part of transplant oncologists and dentists as well as more aggressive preventive measures are warranted, as well as prospective studies to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of preventive interventions.

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

  Authors: Paul J Martin, J Douglas Rizzo, John R Wingard, Karen Ballen, Peter T Curtin, Corey Cutler, Mark R Litzow, Yago Nieto, Bipin N Savani, Jeffrey R Schriber, Paul J Shaughnessy, Donna A Wall, Paul A Carpenter

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of acute GVHD, 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 acute GVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of acute GVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Since the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous studies and the design of future studies.

• Secondary Treatment of Acute Graft-versus-host Disease: A Critical Review.

  Authors: Paul J Martin, Yoshihiro Inamoto, Mary E D Flowers, Paul A Carpenter

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Management of steroid-resistant or steroid-refractory acute GVHD poses one of the most vexing and difficult problems faced by transplant physicians. In the current study, we used 10 criteria toManagement of steroid-resistant or steroid-refractory acute GVHD poses one of the most vexing and difficult problems faced by transplant physicians. In the current study, we used 10 criteria to evaluate 67 reports describing secondary treatment of acute GVHD. The goal of this exercise was not only to provide a critical summary of the literature but also to offer suggestions that could improve future studies. Areas especially in need of improvement include the use of a consistent treatment regimen, the assessment of response at a consistent prespecified time point, consideration of concomitant treatment in assessing response, documentation that selection bias was minimized, and the use of methods that test a formal statistical hypothesis based on a contemporaneous or historical benchmark. Our results suggest that previous published reports collectively offer little guidance in discerning the most effective treatments for patients with steroid-resistant or steroid-refractory acute GVHD. Adherence to the proposed criteria in future reports would enable meaningful comparisons across studies and thereby accelerate progress in evaluating new treatments for acute GVHD.

• ASBMT POSITION STATEMENT The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Pediatric Acute Lymphoblastic Leukemia: Update of the 2005 Evidence-Based Review.

  Authors: Theresa Hahn

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

• Costs and cost-effectiveness of allogeneic stem cell transplantation in children are predictable.

  Authors: S Matthes-Martin, U Pötschger, R D Barr, M Martin, H Boztug, T Klingebiel, A Attarbaschi, W Eibler, G Mann

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  The overall costs of pediatric stem cell transplantation (SCT), including donor search and the first year post SCT in a cohort of 141 consecutive children transplanted in a single institution, wereThe overall costs of pediatric stem cell transplantation (SCT), including donor search and the first year post SCT in a cohort of 141 consecutive children transplanted in a single institution, were calculated. Costs were correlated with patient and transplant characteristics, and a risk score for transplant-related mortality (TRM). Cost-effectiveness was calculated as overall costs per surviving patient. Life-years gained were extrapolated from the overall survival, and the costs per expected lifeyear gained were calculated. Overall median cost was 136,382€ with a wide range from 26,897€ to 601,348€. Costs increased significantly with age, the use of donors other than matched siblings and with advanced disease. There was a strong correlation of costs with a simple TRM risk-score: the median total costs were 89,550€ (score 0), 127,349€ (score 1), 156,578€ (score 2) and 274,915€ (score 3) (p < 0.001). Cost-effectiveness decreased with increasing TRM risk-score: the costs per survivor increased from 93,209€ (score 0) to a maximum of 1,216,348€ (score 3). Costs of pediatric SCT vary substantially; however the combination of the three variables - age, disease and donor type - is predictive for costs and cost-effectiveness. Costs per life-year gained are within the broadly accepted range in life-threatening hemato-oncologic diseases, even in the most cost-intensive patient cohort.

• Multi-center experience using total lymphoid irradiation and anti-thymocyte globulin as conditioning for allografting in hematological malignancies.

  Authors: Giuseppe Messina, Luisa Giaccone, Moreno Festuccia, Giuseppe Irrera, Ilaria Scortechini, Roberto Sorasio, Federica Gigli, Roberto Passera, Irene Cavattoni, Andrea Riccardo Filippi [......] Nicola Mordini, Andrea Gallamini, Rocco Pastano, Marco Casini, Massimo Aglietta, Mauro Montanari, Giuseppe Console, Mario Boccadoro, Umberto Ricardi, Benedetto Bruno

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  BACKGROUND: A non-myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). DESIGN: And MethodsBACKGROUND: A non-myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). DESIGN: And Methods To evaluate the effects of TLI-ATG in a multi-center study, 45 heavily pre-treated patients, median age 51, with lymphoid (n=38) and myeloid (n=7) malignancies were enrolled at 9 Centers. Twenty-height (62%) received at least 3 lines of treatment before allografting and 13 (29%) had refractory/relapsed disease at the time of transplant. Peripheral blood hematopoietic cells were from HLA identical sibling (n=30), HLA-matched (n=9) or one antigen HLA-mismatched (n=6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. RESULTS: Donor engraftment was reached in 95% of patients. Grade II-IV acute GVHD developed in 6 patients (13.3%), in 2 of these patients beyond day 100. Incidence of chronic GVHD was 35.8%. One-year non relapse mortality was 9.1%. After a median follow up of 28 (range 3-57) months from transplant, median overall survival was not reached whereas median event-free survival was 20 months. CONCLUSIONS: This multi-center experience confirms that TLI-ATG protects against GVHD and maintains graft-versus-tumor effects.

• Costs and Cost-Effectiveness of Hematopoietic Cell Transplantation.

  Authors: Jaime Preussler, Ellen M Denzen, Navneet S Majhail

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

• Allogeneic hematopoietic stem cell transplantation for adult over 40 years old with acquired aplastic anemia.

  Authors: Hawk Kim, Kyoo-Hyung Lee, Sung-Soo Yoon, Sang Kyun Sohn, Young Don Joo, Sung Hyun Kim, Byung Soo Kim, Jung Hye Choi, Jae Youg Kwak, Myung Soo Hyun, Sung Hwa Bae, Ho Jin Shin, Jong Ho Won, Sukjoong Oh, Won Sik Lee, Jae-Hoo Park, Chul Won Jung

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Although younger age is associated with favorable prognosis in adults undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) for aplastic anemia (AA), other pre-transplant factorsAlthough younger age is associated with favorable prognosis in adults undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) for aplastic anemia (AA), other pre-transplant factors may be more important than age. We retrospectively analyzed the impact of older age on transplantation outcomes and survival in total 225 adult AA patients who underwent alloHSCT, 57 patients >40 years old (older patient group; OPG) and 168 patients ≤40 years old (younger patient group; YPG). Age at alloHSCT ≤40 years, time from diagnosis to alloHSCT ≤6 months and matched related donor (MRD) were favorable prognostic factors in all study patients. Risk analysis of survival in the OPG showed that age >50 years was the only poor prognostic factor. Survival did not differ significantly between the YPG and patients <50 years in the OPG. In conclusion, patients between the ages of 41 and 50 years with severe AA and MRDs should undergo allogeneic stem cell transplant as early as possible to optimize survival.

• GVHD-Related, Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15-Positive Target Cells.

  Authors: Qian Zhan, Robert Korngold, Cecilia Lezcano, Frank McKeon, George F Murphy

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  Acute graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation, involves cytotoxic soluble and cellular effectors that induce apoptosis selectively in normallyAcute graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation, involves cytotoxic soluble and cellular effectors that induce apoptosis selectively in normally apoptosis-resistant, cytokeratin 15 (K15)-expressing epithelial stem cells that reside at tips of rete ridges of human epidermis and in analogous rete-like prominences (RLPs) of murine dorsal lingual epithelium. The mechanism(s) whereby epithelial stem cells are rendered vulnerable to apoptosis during allostimulation is unknown. We hypothesized that GVHD-induced target cell injury may relate 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 p73 protein and mRNA to be preferentially expressed in K15+ RLPs of murine lingual squamous epithelium. Upon in vitro exposure to recombinant TNF alpha (TNF〈) 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. These data for the first time indicate 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.

• A multi-center, randomized, open label study comparing the efficacy and safety of micafungin vs. itraconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplantation.

  Authors: Xiaojun Huang, Huan Chen, Mingzhe Han, Ping Zou, Depei Wu, Yongrong Lai, He Huang, Xiequn Chen, Ting Liu, Huanling Zhu, Jianmin Wang, Jianda Hu

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  BACKGROUND: This multicenter, randomized, open-label phase 3 study compared the efficacy and safety of micafungin and itraconazole in prophylaxis of invasive fungal infections (IFI) in neutropenicBACKGROUND: This multicenter, randomized, open-label phase 3 study compared the efficacy and safety of micafungin and itraconazole in prophylaxis of invasive fungal infections (IFI) in neutropenic patients undergoing hematopoietic stem cell transplantation in China. METHODS: Micafungin (50mg/day i.v.) or itraconazole (5mg/kg/day p.o.) was administered for ≤ 42 days. The primary endpoint, treatment success, was defined as no proven, probable or suspected IFI through therapy and the absence of proven or probable IFI through the end of 4 weeks after therapy. Non-inferiority of micafungin against itraconazole was established if the lower boundary of 95% CI was > -10%. RESULTS: Of 287 patients, 283 were evaluable for efficacy (136 for micafungin, 147 for itraconazole, intent-to-treat population). Treatment success was documented in 92.6% (126/136) of micafungin-treated patients and 94.6% (139/147) of itraconazole-treated patients: 95% CI, -7.562 to 3.482% (P=0.48) indicating non-inferiority of micafungin against itraconazole. Results were similar for patients treated per protocol. While rates of proven or probable IFI were numerically higher with micafungin than itraconazole at 4.4% (6/136) and 1.4% (2/147), rates of suspected IFI were similar at 5.9% (8/136) and 7.5% (11/147), respectively. More patients treated with micafungin than itraconazole completed the study (82.9 vs. 67.3%, respectively). Significant differences in incidence of withdrawal due to an adverse event (4.4 vs. 21.1%) and drug-related adverse events (8 vs. 26.5%) were shown between micafungin and itraconazole (P=0.00, chi-square test). CONCLUSION: Micafungin was as effective as itraconazole in preventing IFI in neutropenic patients. In comparison to itraconazole, treatment tolerance was much better with micafungin. [word count = 250].

• TNF-inhibition with etanercept for graft versus host disease prevention in high risk HCT: Lower TNFR1 levels correlate with better outcomes.

  Authors: Sung W Choi, Patrick Stiff, Kenneth Cooke, James L M Ferrara, Thomas Braun, Carrie Kitko, Pavan Reddy, Gregory Yanik, Shin Mineishi, Sophie Paczesny, David Hanauer, Attaphol Pawarode, Edward Peres, Tulio Rodriguez, Scott Smith, John E Levine

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  PURPOSE: Graft-versus-host disease (GVHD) causes most non-relapse mortality (NRM) following alternative donor (unrelated and mismatched related) hematopoietic cell transplant (HCT). We previouslyPURPOSE: Graft-versus-host disease (GVHD) causes most non-relapse mortality (NRM) following alternative donor (unrelated and mismatched related) hematopoietic cell transplant (HCT). We previously showed that increases in day +7 TNF-receptor-1 (TNFR1) ratios (post-transplant day +7/pre-transplant baseline) after myeloablative HCT correlate with outcomes including GVHD, NRM and survival. Therefore, we conducted a phase II trial at two centers testing whether the addition of the TNF-inhibitor etanercept (25 mg twice weekly from start of conditioning to day +56) to standard GVHD prophylaxis would lower TNFR1 levels, reduce GVHD rates, and improve NRM and survival. PATIENTS AND METHODS: Patients underwent myeloablative HCT from a matched unrelated donor (N=71), one-antigen mismatched unrelated donor (N=26) or one-antigen mismatched related donor (N=3) using either total body irradiation (TBI)-based conditioning (N=29) or non-TBI-based conditioning (N=71). RESULTS: Compared to historical controls, the increase in post-transplant day +7 TNFR1 ratios was not altered in patients who received TBI-based conditioning, but was 40% lower in patients receiving non-TBI-based conditioning. The latter group experienced relatively low rates of severe grade 3-4 GVHD (14%), one-year NRM (16%), and high one-year survival (69%). CONCLUSIONS: These findings suggest that (1) the effectiveness of TNF-inhibition with etanercept may depend on the conditioning regimen, and (2) attenuating the expected rise in TNFR1 levels early post-transplant correlates with good outcomes.

• Melphalan 180mg/m2 can be safely administered as Conditioning Regimen prior to an Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma Patients with Creatinine Clearance 60ml/min/1.73 m2 or lower with use of palifermin for Cytoprotection: Results of a Phase I Trial.

  Authors: Muneer H Abidi, Rishi Agarwa, Lois Ayash, Abhinav Deol, Zaid Al-Kadhimi, Judith Abrams, Simon Cronin, Marie Ventimiglia, Lawrence Lum, Voravit Ratanatharathorn, Joseph Uberti

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

  BACKGROUND: High-dose melphalan (M) 140 mg/m(2) is the standard of care for multiple myeloma(MM) patients (pts) with renal insufficiency (RI). Palifermin (P) as a cytoprotective agent hasBACKGROUND: High-dose melphalan (M) 140 mg/m(2) is the standard of care for multiple myeloma(MM) patients (pts) with renal insufficiency (RI). Palifermin (P) as a cytoprotective agent has demonstrated efficacy in reducing the intensity and duration of oral mucositis (OM) in pts who receive intensive chemotherapy/radiotherapy. There is no prospective data on the use of P in MM pts with RI. METHODS: Eligibility criteria: creatinine clearance ≤ 60ml/min/1.73 m(2), age >18 years, no dialysis, no active OM and a suitable candidate for ASCT. M dose ranged from 140-200 mg/m(2) and escalated at the increment of 20 mg/m(2). Six dosages of palifermin (P) 60 mcg/kg/d were given intravenously between day-5 to day+3. Dose escalations were to stop if dose- limiting toxicities (DLTs) occurred at M dose in ≥ 2/3 pts, with that dose declared as the maximal administered dose and the level below where ≤ 1/6 pts had DLTs was considered MTD. RESULTS: Nineteen pts were enrolled from 06/2007 to 06/2011. Data on 15 evaluable pts is reported as 4 pts were removed. Median age was 59 years (36-67y). The overall incidence of OM ≥ grade 3 was 53% (8/15) and a median duration of ≥ grade 3 OM was 6.5 days (3 - 42). One patient in L2 (M 160 mg/m(2)) developed atrial fibrillation on Day+9. Two pts in L4 (M 200mg/m(2)) developed grade 4 OM, hence reaching DLT. No DLT was observed in 6 pts enrolled in L3 (M 180mg/m(2)). CONCLUSIONS: P has permitted safe dose escalation of M up to 180 mg/m(2) in RI pts.

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