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tested to illuminate mechanisms underlying the inflammation, dysregulated repair, and collagen deposition characteristic of OLD and RLD [7,8]. Furthermore, new strategies, including the administration of etanercept (a soluble TNFaebinding protein) and combination therapy with fluticasone, azithromycin, and montelukast (FAM), have shown promise [9] and are currently undergoing further testing [10]. More remains to be done, however. For starters, consistent approaches to the monitoring of pulmonary function (including the utility of expanded use of hand-held spirometry) after allogeneic HCT, diagnostic workup (including the roles of bronchoscopy and computed tomography) of affected patients, and classification of lung dysfunction (particularly RLD) once identified, along with clinical guidelines for the initiation of inhaled or systemic therapy, are lacking and need to be established. Furthermore, advances in radiographic imaging that may allow earlier detection of progressive parenchymal or small airway inflammation [11] and overcome limitations of available diagnostic tools should be explored in allogeneic HCT recipients with suspected OLD or RLD. Thus, steps to address “boring” but critical knowledge gaps in standard of practice can be complemented by cutting-edge technology and provide a platform to determine whether early detection of pulmonary dysfunction will enhance the success of timely intervention with novel immunomodulatory therapy. The addition of patient sample procurement (ie, bronchoalveolar lavage fluid, plasma, and stool) at defined time points in such an endeavor will allow for clinical biomarker discovery and exploration of nonconventional infectious etiologies of OLD and RLD using next-generation sequencing techniques as described for other HCT complications [12,13]. Despite the tremendous advances in transplantation biology and clinical care over the last several decades, cGVHD and pulmonary toxicity remain the scourges of allogeneic HCT recipients, negatively impacting quality of life and limiting successful outcomes. It is hoped that future exploration using animal models and the development of innovative and comprehensive clinical trials will allow investigators to better define and exploit the window of opportunity for patients with late-onset pulmonary

dysfunction opened by the results of the study reported by Palmer and colleagues. ACKNOWLEDGMENTS Financial disclosure: The author has nothing to disclose. REFERENCES 1. Palmer J, Williams K, Inamoto Y, et al. Pulmonary symptoms measured by the NIH lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic GVHD. Biol Blood Marrow Transplant. 2014;20:336-343. 2. Yoshihara S, Yanik G, Cooke KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13:749-759. 3. Williams KR, Chien JW, Gladwin MT, et al. Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. JAMA. 2009;302: 306-314. 4. Hildebrandt GC, Fazekas T, Lawitschka A, et al. Diagnosis and treatment of pulmonary chronic GVHD: a report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant. 2011;46: 1283-1295. 5. Martin PJ, Chen JW. What we know and mostly do not know about bronchiolitis obliterans syndrome. Bone Marrow Transplant. 2012;47:1-4. 6. Sengayadeth SM, Srivastava S, Jagasia M, et al. Time to explore preventative and novel therapies for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:1479-1487. 7. Panoskaltsis-Mortari A, Tram KV, Price AP, et al. A new murine model for bronchiolitis obliterans post-bone marrow transplant. Am J Respir Crit Care Med. 2007;176:713-723. 8. Yanik G, Cooke KR. The lung as a target organ of graft-versus-host disease. Semin Hematol. 2006;43:42-52. 9. Yanik GA, Mineishi S, Levine JE, et al. Soluble tumor necrosis factor receptor: Enbrel (etanercept) for sub-acute pulmonary dysfunction following allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:1044-1054. 10. Williams KM, Pavletic SZ, Lee JS, et al. Interim analysis of a phase II trial of montelukast for the treatment of bronchiolitis obliterans syndrome after HSCT reveals immunobiology of disease. Biol Blood Marrow Transplant. 2013;19(Suppl 2):S143. 11. Galban CJ, Han MK, Boes JL, et al. Computed tomographyebased biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med. 2012;18:1711-1715. 12. Vander Lugt MT, Braun TM, Hanash S, et al. ST2 as a marker for risk of therapy-resistant GVHD and death. N Engl J Med. 2013;369:529-539. 13. Bhatt AS, Freeman SS, Herrera AF, et al. Sequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome. N Engl J Med. 2013; 369:517-528.

Antithymocyte Globulin in Reduced-Intensity Conditioning Allografting: Is the Benefit Simply in the Eyes of the Transplanter? Mehdi Hamadani* Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin

Article history: Received 20 December 2013 Accepted 28 December 2013

Financial Disclosure: None relevant to the article. * Correspondence and reprint requests: Mehdi Hamadani, MD, Associate Professor of Medicine, Division of Hematology & Oncology, Medical College of Wisconsin & CIBMTR, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. E-mail address: [email protected] 1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2013.12.571

In the modern era, graft-versus-host disease (GVHD) and associated nonrelapse mortality (NRM) continue to plague allogeneic hematopoietic cell transplantation (allo-HCT) outcomes. A variety of strategies has been developed to prevent GVHD after allo-HCT, including ex vivo or in vivo T cell depletion, pharmacological inhibition of T cell proliferation or trafficking, monoclonal antibodies, and immune-modulation (to name a few), but the best prophylactic modality remains controversial. In vivo T cell depletion with antithymocyte globulin (ATG) is commonly performed by administering 1 of 3 commercially


available products (Thymoglobulin [Genzyme Corporation, Cambridge, MA], ATGAM [Pfizer, New York, NY], or ATG-Fresenius [Fresenius Biotech GmbH, Germany]) [1]. ATG prevents GVHD not only through in vivo donor effector T cell depletion but also via pleiotropic effects on the immune system, including depletion and modulation of antigenpresenting cells, modulation of cell surface molecules that mediate leukocyte/endothelium interactions, and induction of regulatory T cells [2,3]. The efficacy of ATG in preventing GVHD is intricately dependent not only on the dose and type of ATG preparation used and on the timing of ATG administration, but also on transplant characteristics including the type of donor (sibling versus unrelated) and graft (bone marrow versus peripheral blood) source used, degree of HLA matching, and intensity of conditioning regimens. The complex interplay of so many confounding variables affecting the efficacy of ATG makes interpreting data of clinical trials evaluating the role of ATG as GVHD prophylaxis problematic. A meta-analysis [4] of seven randomized studies [5-8] using mostly myeloablative conditioning regimens and an invariably heterogeneous patient population (in terms of ATG preparation, disease type, donor and stem cell source, etc.), showed reduced rates of grades III to IV acute GVHD in patients receiving ATG, but without any reduction in the rates of grades I to II acute GVHD, NRM, or an overall survival benefit. Although the above meta-analysis [4] and some randomized trials [5] suggest that in the setting of unrelated donor myeloablative transplantation, ATG can mitigate the risk of GVHD without negatively affecting survival outcomes, extrapolating these data to reduced-intensity conditioning (RIC) allo-HCT, without supporting randomized data, warrants careful reappraisal. In this issue of Biology of Blood and Marrow Transplantation, Devillier et al. [9] report retrospective outcomes of 209 patients undergoing RIC allo-HCT with fludarabine, busulfan, and thymoglobulin. Sixty percent of included patients underwent matched sibling HCT. Using a total thymoglobulin dose of 5 mg/kg, the authors report grades III to IV acute and extensive chronic GVHD rates of 9% and 22%, respectively. Four-year NRM, relapse rate, and overall survival rates were 22%, 36%, and 54%, respectively. Infections notably accounted for most NRM (34 of 43 events). This study, in line with previously published uncontrolled reports, suggests acceptable allo-HCT outcomes after ATG-based RIC. However, key questions remain unanswered regarding the superiority of this approach (compared with other non-ATGecontaining options), optimal dose intensity of thymoglobulin, suitable patient population, and the impact of this approach on posttransplant disease control, infectious complications, immune reconstitution, and survival outcomes. The lack of randomized trials demonstrating benefit of ATG as GVHD prophylaxis in RIC allo-HCT cannot be overemphasized. Soiffer et al. [10] examined the impact of ATG use on outcomes of RIC allo-HCT in a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis. Compared with patients receiving a T cellereplete graft, ATG use in this important study did not reduce the rates of grades II to IV (40% versus 38%) and III to IV acute GVHD (22% versus 21%). This CIBMTR analysis [10], the report by Devillier et al. [9], and others have shown low rates of chronic GVHD with the inclusion of ATG in RIC. It is important to note, however, that these studies predominantly used peripheral blood grafts. Whether the same degree of benefit could be derived by preferentially using bone marrow as an unrelated donor

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allograft source, with its associated reduced risk of chronic GVHD [11], is not clear. The use of ATG has not been shown to be associated with a higher risk of disease relapse in patients undergoing myeloablative allo-HCT [4], a situation where the intensity of conditioning contributes significantly toward post-HCT disease control. Whether ATG is detrimental for disease control in RIC allografts, that primarily relying on conditioning intensity depends more heavily on graft-versus-malignancy effects mediated by donor T cells (a subset likely impacted by in vivo T cell depletion), merits careful consideration. In the CIBMTR analysis described above [4], increased rates of relapse were observed with ATG use compared with unmanipulated grafts (51% versus 38%, respectively), which in turn resulted in inferior survival outcomes post-RIC allo-HCT. Despite the retrospective nature of the analysis and the biases inherent in registry analyses, this study cautions against the routine use of ATG in RIC regimens. An increased risk of relapse is a particularly important consideration for patients with high or very-high disease risk index, as illustrated by higher relapse rates of such patients in the study by Devillier et al. [9]. The optimal dose intensity of thymoglobulin in RIC alloHCT is poorly defined. Mohty et al. [12], in a series of patients undergoing (matched sibling) allo-HCT, observed a significant increase in rates of acute and chronic GVHD when thymoglobulin dose was reduced from 7.5 mg/kg to 2.5 mg/kg. We have previously shown that reduction of thymoglobulin dose from 7.5 mg/kg to 6 mg/kg in RIC unrelated donor HCT maintains GVHD control and may favorably affect NRM. Devillier and colleagues should be commended for their continued efforts in further defining the optimal dose intensity of thymoglobulin (ie, w5 mg/kg) in RIC allografts [8,13,14]. Collectively, these data suggest that if incorporated in RIC regimens, thymoglobulin doses should not exceed the 5- to 6-mg/kg (total dose) range. These assumptions obviously do not apply to nonthymoglobulin ATG preparations. When compared with higher doses (7.5 mg/kg), reduced thymoglobulin doses do appear to be associated with a reduced risk of infectious complications. It is important to remember, however, that these risks are by no means insignificant. Patients receiving thymoglobulin with RIC allo-HCT remain susceptible to frequent viral reactivations, fungal and bacterial infections, and post-transplant lymphoproliferative disorders, all of which require significant post-transplant resource utilization for monitoring and treatment. This fact needs to be considered when applying in vivo T cell depletion, especially in matched sibling allografts, where risk of GVHD is relatively lower. Prospective trials comparing ATG-based prophylaxis against novel GVHD preventive strategies [15-17] for patients undergoing RIC (from uniform donor and stem cell sources) are unlikely to be performed. In the absence of such high-quality randomized data, the decision to include ATG in RIC allo-HCT will be directed largely by transplant center and treating physician preference. Although proponents of this approach cite low rates of acute and chronic GVHD and possibly less frequent infectious complications with lower ATG doses as reasons to include in vivo T cell depletion in RIC programs, opponents will continue to highlight compromised disease control, significant infectious complications, delayed immune reconstitution, and the lack of any demonstrable overall survival benefit or quality-of-life improvement with ATG use as arguments against this

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strategy. It appears that, like beauty, the benefits of ATG lie largely in the eye of the beholder (or transplanter).

REFERENCES 1. Hamadani M, Blum W, Phillips G, et al. Improved nonrelapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced-intensity conditioning allogeneic transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2009;15:1422-1430. 2. Feng X, Kajigaya S, Solomou EE, et al. Rabbit ATG but not horse ATG promotes expansion of functional CD4þCD25highFOXP3þ regulatory T cells in vitro. Blood. 2008;111:3675-3683. 3. Haidinger M, Geyeregger R, Poglitsch M, et al. Antithymocyte globulin impairs T-cell/antigen-presenting cell interaction: disruption of immunological synapse and conjugate formation. Transplantation. 2007;84: 117-121. 4. Kumar A, Mhaskar AR, Reljic T, et al. Antithymocyte globulin for acutegraft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review. Leukemia. 2012;26:582-588. 5. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, openlabel, multicentre phase 3 trial. Lancet Oncol. 2009;10:855-864. 6. Champlin RE, Perez WS, Passweg JR, et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood. 2007;109:4582-4585. 7. Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98:2942-2947.

8. Ramsay NK, Kersey JH, Robison LL, et al. A randomized study of the prevention of acute graft-versus-host disease. N Engl J Med. 1982;306: 392-397. 9. Devillier R, Fürst S, El-Cheikh J, et al. Antithymocyte globulin in reduced intensity conditioning regimen allows a high disease-free survival exempt of long term chronic GVHD. Biol Blood Marrow Transplant. 2014;20:369-373. 10. Soiffer RJ, LeRademacher J, Ho V, et al. Impact of immune modulation with antieT-cell antibodies on the outcome of reduced intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood. 2011;117:6963-6970. 11. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487-1496. 12. Mohty M, Bay JO, Faucher C, et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood. 2003;102:470-476. 13. Crocchiolo R, Esterni B, Castagna L, et al. Two days of antithymocyte globulin are associated with a reduced incidence of acute and chronic graft-versus-host disease in reduced-intensity conditioning transplantation for hematologic diseases. Cancer. 2013;119:986-992. 14. Devillier R, Crocchiolo R, Castagna L, et al. The increase from 2.5 to 5 mg/kg of rabbit anti-thymocyte-globulin dose in reduced intensity conditioning reduces acute and chronic GVHD for patients with myeloid malignancies undergoing allo-SCT. Bone Marrow Transplant. 2012;47:639-645. 15. Hamadani M, Gibson LF, Remick SC, et al. Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graft-versus-host disease. J Clin Oncol. 2013;31:4416-4423. 16. Reshef R, Luger SM, Hexner EO, et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med. 2012;367:135-145. 17. Koreth J, Stevenson KE, Kim HT, et al. Bortezomib-based graft-versushost disease prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol. 2012;30:3202-3208.