Graft Versus Host Disease for the General Oncologist

The Journal of Targeted Therapies in CancerJune 2014
Volume 3
Issue 3

Allogeneic hematopoietic cell transplant (alloHCT) can be a mysterious process for patients and general oncologists.

George Chen, MD

Roswell Park Cancer Institute

Elm and Carlton Streets

Buffalo, NY 14263

716 845 8722


Allogeneic hematopoietic cell transplant (alloHCT) can be a mysterious process for patients and general oncologists. Patients are referred to transplant centers that are sometimes far from their residences, travel there to receive therapy, and return with new immune systems and a new set of potentially lifethreatening complications of which they must be aware. Graft versus host disease (GvHD) is the most common complication of alloHCT. With the rising number of alloHCTs performed yearly for broader indications, general oncologists are increasingly likely to encounter GvHD. This article will review the pathophysiology of GvHD as well as general principles of treatment.

Since its first report in 1968 by Thomas and Ferrebee et al, hematopoietic cell transplantation (HCT) has evolved into a standard therapy used in the treatment of many hematologic and oncologic disorders.1HCT can utilize autologous (self) or allogeneic (non-self) hematopoietic cells. The purpose of autologous HCT (autoHCT) is to rescue patients from the marrow ablative effects of high-dose chemotherapy. AutoHCT is used to treat malignancies such as germ cell tumors, selected cases of non-Hodgkin and Hodgkin lymphoma, and multiple myeloma, which have steeply positive dose versus response curves. In contrast, allogeneic HCT (alloHCT) is used to provide an immune effect against the underlying malignancy, as well as to restore hematopoiesis that has been destroyed by chemotherapy preparative and therapeutic regimens. Disorders for which alloHCT has been incorporated as a standard therapy include acute myeloid and lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative diseases, aplastic anemia, and certain inherited bone marrow disorders.

Graft versus host disease (GvHD) is the immunologic reaction of the donor’s cells (the graft) against the recipient’s body (the host). In 1966, RE Billingham succinctly postulated the necessary conditions for the development of GvHD as follows: 1) the recipient must be immunologically disparate from the donor; 2) the donor cells must be capable of recognizing these immunologic disparities; and 3) the donor cells must be able to persist and function in the recipient.2These postulates have been largely borne out: the incidence of GvHD is extremely rare to nonexistent in autologous HCT; the incidence is reduced when the donor graft has not completely replaced the recipient’s hematopoietic system and it coexists with residual recipient hematopoietic cells in a state of mixed donor chimerism3; and, finally, immunosuppressive combination therapies can prevent the development of GvHD.4

Approximately 7000 alloHCTs are performed annually in the United States. Fifty percent of these will develop some form of GvHD.5The incidence of GvHD is predicted to increase in the next several years due to the increased use of peripheral blood grafts as opposed to bone marrow grafts,6increasing donor and recipient age,5and the increased use of HLA-mismatched and haploidentical donors.7

Acute Graft Versus Host Disease

Graft versus host disease can be classified as acute or chronic. Classically, acute and chronic GvHD (aGvHD, cGvHD) have been defined based upon their onset before or after day 100, respectively. More recently, because of the increasing recognition that cGvHD is pathophysiologically distinct from aGvHD, the two have been differentiated on the basis of their presenting symptoms.8Acute GvHD is characterized by dermatitis, hepatitis, and colitis. It can also present with upper gastrointestinal symptoms of anorexia and nausea.9Therapy to control aGvHD occurs in 2 phases: prophylaxis and treatment. Without prophylaxis, all alloHCT patients will develop aGvHD.10 Prophylaxis of aGvHD utilizes a variety of strategies to suppress the activity of T cells, which are thought to be the primary drivers of aGvHD. Pharmacologic strategies use agents such as a calcineurin inhibitor and methotrexate. Prophylaxis with regimens such as tacrolimus (TAC)/methotrexate (MTX) and TAC/micro-dose MTX/mycophenolate mofetil (MMF) can prevent aGvHD in 50% to 65% of alloHCT recipients.11-14Cellular strategies deplete T cells, either ex vivo or in vivo, such as with cyclophosphamide and antithymocyte globulin (ATG).15-17

Clinical Pearls

  • Chronic GvHD (cGvHD) symptoms of cutaneous sclerotic disease, eye and mouth dryness, gastrointestinal symptoms, and shortness of breath can present insidiously at any time after alloHCT. Community oncologists are the first line of detection and can greatly contribute to the well-being of their patients who have undergone alloHCT.
  • The decision to treat cGvHD with systemic therapy must take into consideration the patient’s risk for disease relapse as well as tolerance of his/her cGvHD manifestations.
  • Referral back to the transplant center is important for further discussion of diagnostic and therapeutic options.

Even with prophylaxis, 35% to 47% of alloHCT patients will develop aGvHD. Primary therapy for aGvHD is glucocorticoids. Methylprednisolone (or its equivalent) is typically initiated at the dose of 2 mg/kg/day. If the patient is receiving a calcineurin inhibitor, the dose is maximized to prevent further development of aGvHD. Improvement in symptoms will typically occur within 5 days. Once symptoms improve, the dose of glucocorticoids is gradually reduced by 20% to 25% every 3 to 4 days. Once the dose reaches 0.5 mg/kg, tapering usually slows to 10% decrements until the glucocorticoids are discontinued. Tapering of calcineurin inhibitors usually follows afterward.

Approximately 50% of patients will respond to primary therapy for aGvHD.11,12,18,19The remainder progress to second-line therapies, such as ATG, rituximab, pentostatin, etanercept, tocilizumab, and alemtuzumab. There is no clearly superior second-line therapy and each successive agent begets a progressively lower response rate. Approximately 5% to 10% of patients undergoing alloHCT will die from complications of aGvHD. These complications are often related to uncontrolled infections exacerbated by the immunosuppression needed to treat aGvHD.

Chronic Graft Versus Host Disease

General oncologists are unlikely to administer aGvHD prophylaxis or treatment because aGvHD typically occurs in the immediate posttransplant period while the patient is under the active care of the transplant service. However, it is possible for general oncologists to encounter patients with aGvHD symptoms in the setting of additional therapy for relapsed disease after alloHCT. Usually, this would consist of chemotherapy or a donor lymphocyte infusion, which would be given after the initial transplant in order to treat recurrent disease, prevent relapse, or to enhance engraftment of donor hematopoietic cells. In this situation, prompt recognition of the classic triad with confirmatory biopsy and initiation of glucocorticoid therapy or referral back to the transplant center are important.In contrast to aGvHD, general oncologists are more likely to encounter cGvHD. After the infusion of the allogeneic donor graft, patients are closely followed by the transplant service for any potential complications, such as aGvHD, infection, and graft failure, for approximately 100 days. After this period and in the absence of ongoing complications, patients are referred back to the primary oncologist for shared follow-up. Patients often live far from the transplant center and present first to their primary local oncologist with late transplant- related complications. Also, because many of the presenting symptoms of cGvHD are not typically associated with oncologic diseases, primary oncologists may be the first to notice a change in recipients of alloHCT. In this setting, early detection of cGvHD manifestations can speed diagnosis and therapy of cGvHD and greatly contribute to the continued well-being of patients. In fact, a study of patients’ self-perceptions of their own well-being before and after effective cGvHD therapy indicated that they felt as well after successful therapy of cGvHD as if they had not developed cGvHD at all.20This underscores the need to treat as well as discover new ways to treat cGvHD.

Chronic GvHD is characterized by immune dysfunction, glandular destruction, and multi-organ fibrosis. It typically manifests as skin, lung, eye, and mouth disease that is reminiscent of autoimmune disorders. Cutaneous disease is the most common manifestation and occurs in 75% of cGvHD. The skin can be hyperpigmented, lichenoid, or sclerodermatous, resulting in skin thickening and loss of elasticity.21Shoulder, wrist, and ankle range of motion is often decreased because of limitations imposed by sclerodermatous skin surrounding the joint, as well as fibrosis of the underlying soft tissue. The lungs can present with fibrosis and decreased compliance. The eyes and mouth are typically sensitive and dry with a gritty feeling similar to Sjögren’s syndrome. These manifestations can negatively impact the health of alloHCT survivors with marked discomfort, functional impairment, and pain.

Recipients of alloHCT will often imperceptibly develop the symptoms of cGvHD. Clues to suggest nascent cGvHD often relate to its sclerotic manifestations. Patients will often complain of increased joint stiffness but not necessarily decreased joint mobility. They may have more trouble than usual reaching overhead cabinets or putting on sweaters because of impaired shoulder range of motion. They may have trouble with fine work using their fingers, such as handling small and delicate objects like eyeglasses, due to sclerosis of the forearm, wrist tendons, and ligaments. Thickening of midsection skin is often seen. These patients may notice that they have trouble bending over to tie their shoelaces. Patients who play golf may notice that their swing is not as effective as it once was because they cannot rotate as well. They may feel that they have difficulty reaching behind them, such as while putting objects in their back pockets. Severe cases of sclerodermal disease located in the midsection will result in decreased appetite secondary to early satiety due to restriction of abdominal expansion in response to food. Patients with cGvHD of the lungs may notice increased shortness of breath with mild exertion. Recovery from pulmonary infections may be prolonged and colonization with multiresistant Pseudomonas may occur. Finally, patients may notice increased eye irritation as well as oral sensitivity to eating crunchy, salty, or spicy foods. They may subconsciously begin avoiding their favorite spicy foods.

The onset of cGvHD can be slow and gradual over months. Sometimes, cGvHD presents acutely over several days, such as during the tapering of immunosuppression, either given for treatment of preexisting GvHD or for prophylaxis of aGvHD, as well as 1 to 4 weeks after a viral infection. Intense sun exposure can also be followed by a flare of cGvHD.

TABLE 1. Commonly Used Second-Line Therapies for Glucocorticoid-Resistant cGvHD


Overall Responses

Type of Evidence

Proposed Mechanism/Comments

Systemic therapies


7/10 (70%)

Phase I prospective study

Anti-CD52 antibody that results in T-cell depletion


43/71 (61%)

Retrospective study

ECP induces apoptosis of leukocytes, which induce a tolerogenic response when reinfused into the patient


17/32 (53%)

Phase II prospective study

Inhibit binding of peptides to the MHC groove so that peptides cannot shuttle to the cell surface for presentation to T cells; in vitro synergism with cyclosporine and tacrolimus


6/15 (40%) -15/19 (79%)

Phase I prospective studies

Inhibition of platelet-derived growth factor and transforming growth factor-β signal transduction, which results in collagen deposition and fibrosis in mouse models of scleroderma


18/25 (72%) - 7/11 (64%)

Retrospective studies

Reversible inhibitor of inosine monophosphate dehydrogenase, which is the only pathway for purine salvage in lymphocytes


32/58 (55%)

Phase II prospective study

Nucleoside analog that is an irreversible inhibitor of adenosine deaminase, which is essential to purine metabolism and highly active in lymphocytes and macrophages


14/20 (70%) -32/37(86%)

Phase I and II prospective studies

Anti-CD20 antibody depletes B cells that may play a contributory role for cGvHD pathogenesis


22/35 (63%)

Phase II prospective study

Macrocyclic triene antibiotic with immunosuppressive properties; prevents T- and B-cell activation; can work synergistically with tacrolimus and mycophenolate mofetil

Approximately 50% of patients receiving alloHCT will develop some form of cGvHD.22,23Acute GvHD is a major risk factor for later development of cGvHD; onethird of aGvHD patients will develop cGvHD.24Chronic GvHD is a major complication of alloHCT and the most frequent cause of nonrelapse mortality in long-term survivors.25,26Chronic GvHD is thought to arise from the reaction of donor T cells against the recipient’s body tissues, as suggested by decreased cGvHD incidence rates in studies of alloHCT using T-cell—depleted hematopoietic cell grafts.27However, the contribution of other immune cells, such as B cells, NK cells, and dendritic cells, is increasingly recognized, as demonstrated by the use of therapeutic agents targeting these mechanisms.

Chronic GvHD therapy is directed toward correcting the immunologic dysfunction, either by suppressing or modulating the donor immune system, or toward palliation of cGvHD dermatologic, ocular, and oral manifestations. The choice to target the underlying immune dysfunction or the symptoms depends on the patient. The severity of cGvHD has been associated with prolonged overall survival probably due to decreased relapse, possibly from a concomitant graft-versusmalignancy effect.26Any therapy for cGvHD, especially immunosuppressive ones such as glucocorticoids and calcineurin inhibitors, should consider the possible reduction of graft-versus-malignancy effects. Many patients are able to tolerate mild cGvHD symptoms, such as patches of lichenoid skin, or they are able to control the impact of these lesions with symptomatic therapies.



The primary therapy for cGvHD is glucocorticoids and a calcineurin inhibitor, such as tacrolimus.28Therapeutic responses in cGvHD are much slower than in aGvHD and may require several weeks to months. Approximately 50% of patients will not respond and will require second-line therapy. At this time, there is no standard approach to glucocorticoid refractory cGvHD. Many phase I/II studies of secondary therapies for cGvHD have been performed. Commonly used secondary therapies include rituximab, imatinib, hydroxychloroquine, pentostatin, extracorporeal photopheresis (ECP), and sirolimus (Table 1).29-36A phase I study of alemtuzumab in cGvHD has recently been published.37Given the extensive experience with this agent, alemtuzumab is also expected to be increasingly used. The addition of hydroxychloroquine, ECP, and mycophenolate mofetil to standard systemic therapy with a calcineurin inhibitor and prednisone has undergone randomized phase II or phase III testing.35,38,39No benefit was seen with hydroxychloroquine or mycophenolate mofetil, while a slight benefit was seen with ECP. These trials were performed in the setting of first-line therapy of cGvHD rather than as second-line therapy for steroid refractory disease, suggesting that while these agents may not necessarily add to first-line therapy, they may be beneficial in the subgroup of patients dependent on glucocorticoids. Other agents for which evidence for use exists but which are not frequently used include alefacept, clofazimine, etretinate, halofuginone, low-dose methotrexate, thalidomide, thoracoabdominal radiation, and tocilizumab.40-49Symptoms for ocular cGvHD manifestations may be treated with plugging or cautery of the tear ducts, artificial tears, autologous serum eye drops, and special lenses for ocular cGvHD.Graft versus host disease is the most common complication of alloHCT. Graft versus host disease presents as an acute or chronic illness. General oncologists are more likely to encounter and diagnose cGvHD. A close working relationship between the transplant center and the referring general oncologist is essential in order to optimize the long-term care of alloHCT patients. Therapy of cGvHD should be individualized to the patient based upon the risk for relapse, the patient’s tolerance of cGvHD manifestations, and the pace at which manifestations progress. Primary therapy of cGvHD is a calcineurin inhibitor and glucocorticoids. Responses to therapy occur over 3 to 6 months. Commonly used secondary therapies include rituximab, imatinib, and hydroxychloroquine.The author thanks Philip McCarthy, MD, for reviewing this paper and for helpful discussion.


  1. Thomas ED, Lochte HL, Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy.N Engl J Med. 1957;257(11):491-496.
  2. Billingham RE. The biology of graft-versus-host reactions.Harvey Lect. 1966;62:21-78.
  3. Childs R, Clave E, Contentin N, et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses.Blood. 1999; 94(9):3234-3241.
  4. Chen GL, Zhang Y, Hahn T, et al. Acute GVHD prophylaxis with standarddose, micro-dose or no MTX after fludarabine/melphalan conditioning.Bone Marrow Transplant. 2014;49(2):248-253.
  5. Pasquini MC, Wang Z. Current uses and outcomes of hematopoietic stem cell transplantation. CIBMTR Summary Slides 2010. http://www.cibmtr. org. Accessed June 5, 2014.
  6. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors.N Engl J Med. 2012;367(16):1487-1496.
  7. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.Blood. 2007;110(13):4576-4583.
  8. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.Biol Blood Marrow Transplant. 2005;11(12):945-956.
  9. Weisdorf DJ, Snover DC, Haake R, et al. Acute upper gastrointestinal graft-versus-host disease: clinical significance and response to immunosuppressive therapy.Blood. 1990;76(3):624-629.
  10. Sullivan KM, Deeg HJ, Sanders J, et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation.Blood. 1986;67(4):1172-1175.
  11. Hahn T, McCarthy PL, Jr, Zhang MJ, et al. Risk factors for acute graft-versushost disease after human leukocyte antigen-identical sibling transplants for adults with leukemia.J Clin Oncol. 2008;26(35):5728-5734.
  12. Valcarcel D, Sierra J, Wang T, et al. One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing.Biol Blood Marrow Transplant. 2011;17(5):640-648.
  13. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.Blood. 2000;96(6):2062-2068.
  14. Ratanatharathorn V, Nash RA, Przepiorka D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation.Blood. 1998;92(7): 2303-2314.
  15. Luznik L, O’Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.Biol Blood Marrow Transplant. 2008;14(6):641-650.
  16. Wagner JE, Thompson JS, Carter SL, Kernan NA; for the Unrelated Donor Marrow Transplantation Trial. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial.Lancet. 2005;366(9487):733-741.
  17. Lindemans CA, Chiesa R, Amrolia PJ, et al. Impact of thymoglobulin prior to pediatric unrelated umbilical cord blood transplantation on immune reconstitution and clinical outcome.Blood. 2014;123(1):126-132.
  18. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome.Blood. 1990;75(4):1024- 1030.
  19. Roy J, McGlave PB, Filipovich AH, et al. Acute graft-versus-host disease following unrelated donor marrow transplantation: failure of conventional therapy.Bone Marrow Transplant. 1992;10(1):77-82.
  20. Fraser CJ, Bhatia S, Ness K, et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study.Blood. 2006;108(8):2867-2873.
  21. Lee SJ, Flowers ME. Recognizing and managing chronic graft-versus-host disease.Hematology Am Soc Hematol Educ Program. 2008:134-141.
  22. Lee SJ. New approaches for preventing and treating chronic graft-versushost disease.Blood. 2005;105(11):4200-4206.
  23. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2003;9(4):215-233.
  24. Wagner JL, Seidel K, Boeckh M, Storb R. De novo chronic graft-versus-host disease in marrow graft recipients given methotrexate and cyclosporine: risk factors and survival.Biol Blood Marrow Transplant. 2000;6(6):633-639.
  25. Socie G, Stone JV, Wingard JR, et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry.N Engl J Med. 1999;341(1):14-21.
  26. Lee SJ, Klein JP, Barrett AJ, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse.Blood. 2002;100(2):406-414.
  27. Soiffer RJ, Lerademacher J, Ho V, et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies.Blood. 2011;117(25):6963-6970.
  28. Koc S, Leisenring W, Flowers ME, et al. Therapy for chronic graft-versushost disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone.Blood. 2002;100(1):48-51.
  29. Jacobsohn DA, Chen AR, Zahurak M, et al. Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease.J Clin Oncol. 2007;25(27):4255-4261.
  30. Johnston LJ, Brown J, Shizuru JA, et al. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2005;11(1):47-55.
  31. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease.Blood. 2006;108(2):756-762.
  32. Chen GL, Arai S, Flowers ME, et al. A phase 1 study of imatinib for corticosteroid-dependent/refractory chronic graft-versus-host disease: response does not correlate with anti-PDGFRA antibodies.Blood. 2011;118(15):4070-4078.
  33. Olivieri A, Locatelli F, Zecca M, et al. Imatinib for refractory chronic graftversus- host-disease with fibrotic features.Blood. 2009;114(3):709-718.
  34. Gilman AL, Chan KW, Mogul A, et al. Hydroxychloroquine for the treatment of chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2000;6(3A):327-334.
  35. Martin PJ, Storer BE, Rowley SD, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease.Blood. 2009;113(21):5074-5082.
  36. Stadler M, Ahlborn R, Kamal H, et al. Limited efficacy of imatinib in severe pulmonary chronic graft-versus-host disease.Blood. 2009;114(17):3718- 3719; author reply 3719-3720.
  37. Nikiforow S, Kim HT, Bindra B, et al. Phase I study of alemtuzumab for therapy of steroid-refractory chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2013;19(5):804-811.
  38. Gilman AL, Schultz KR, Goldman FD, et al. Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children’s Oncology Group study.Biol Blood Marrow Transplant. 2012;18(1):84-91.
  39. Flowers ME, Apperley JF, van Besien K, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease.Blood. 2008;112(7):2667-2674.
  40. Parker PM, Chao N, Nademanee A, et al. Thalidomide as salvage therapy for chronic graft-versus-host disease.Blood. 1995;86(9):3604-3609.
  41. Kulkarni S, Powles R, Sirohi B, et al. Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease.Bone Marrow Transplant. 2003;32(2): 165-170.
  42. Lee SJ, Wegner SA, McGarigle CJ, Bierer BE, Antin JH. Treatment of chronic graft-versus-host disease with clofazimine.Blood. 1997;89(7): 2298-2302.
  43. Marcellus DC, Altomonte VL, Farmer ER, et al. Etretinate therapy for refractory sclerodermatous chronic graft-versus-host disease.Blood. 1999;93(1):66-70.
  44. Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease.Biol Blood Marrow Transplant. 2011;17(12):1862-1868.
  45. Pines M, Snyder D, Yarkoni S, Nagler A. Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma.Biol Blood Marrow Transplant. 2003;9(7):417-425.
  46. Shapira MY, Abdul-Hai A, Resnick IB, et al. Alefacept treatment for refractory chronic extensive GVHD.Bone Marrow Transplant. 2009;43(4): 339-343.
  47. Giaccone L, Martin P, Carpenter P, et al. Safety and potential efficacy of low-dose methotrexate for treatment of chronic graft-versus-host disease.Bone Marrow Transplant. 2005;36(4):337-341.
  48. Huang XJ, Jiang Q, Chen H, et al. Low-dose methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.Bone Marrow Transplant. 2005;36(4):343-348.
  49. Robin M, Guardiola P, Girinsky T, et al. Low-dose thoracoabdominal irradiation for the treatment of refractory chronic graft-versus-host disease. Transplantation. 2005;80(5):634-642.
  50. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD.Blood. 2006;107(8): 3074-3080.
  51. Olivieri A, Locatelli F, Zecca M, et al. Imatinib for refractory chronic graftversus- host disease with fibrotic features. Blood. 2009;114(3):709-718.
  52. Busca A, Locatelli F, Marmont F, Audisio E, Falda M. Response to mycophenolate mofetil therapy in refractory chronic graft-versus-host disease.Haematologica. 2003;88(7):837-839.
  53. Lopez F, Parker P, Nademanee A, et al. Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2005;11(4):307-313.
  54. Krejci M, Doubek M, Buchler T, Brychtova Y, Vorlicek J, Mayer J. Mycophenolate mofetil for the treatment of acute and chronic steroidrefractory graft-versus-host disease.Ann Hematol. 2005;84(10):681-685.
  55. Kim SJ, Lee JW, Jung CW, et al. Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study.Haematologica. 2010;95(11):1935-1942.
  56. Couriel DR, Saliba R, Escalon MP, et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease.Br J Haematol. 2005;130(3):409-417.
Related Videos
Related Content