Non-infectious complications after bone marrow transplant: chronic graft-versus-host disease

Non-infectious complications after bone marrow transplant: chronic graft-versus-host disease

What every physician needs to know about chronic graft-versus-host disease after bone marrow transplant:

Definition and incidence

Chronic graft-versus-host-disease (cGVHD) is the leading cause of later non-relapse mortality and morbidity after allo-hematopoietic stem cell transplantation (HCT). CGVHD can occur following acute graft-versus-host-disease (aGVHD), can overlap with aGVHD, or occur without preceding acute GVHD (de novo cGVHD). Although it is associated with decreased quality of life (QOL) and increased mortality, a reduced risk of relapse incidence (that is, graft-versus-tumor) is also reported with cGVHD.

CGVHD is classified as mild, moderate, or severe, depending on the number of organs involved and the degree of individual organ involvement.

CGVHD incidence is reported from 30-50% in HLA-matched sibling donor transplants.

Compared to sibling donor transplant, cGVHD is more frequent in HLA-matched unrelated donor (URD) transplants (50-70%).

CGVHD is less common in adults after double umbilical cord blood transplantation (26% at 2 years), compared to sibling or URD transplant.

Risk factors are as follows:

  • Prior acute GVHD is the most important risk factor for development of subsequent chronic GVHD.

  • Recipient: Older age.

  • Donor: Female gender, especially parous female donor and male recipient.

  • Type of donor: Unrelated or HLA-mismatched allo-HCT.

  • Graft source: Peripheral blood stem cells are associated with higher incidence of cGVHD, compared to bone marrow. Cord blood grafts lead to less cGVHD.

  • High graft CD34+ cell count.

  • Cytomegalovirus (CMV) seropositivity.

  • Donor lymphocyte infusion.

What features of the presentation will guide me toward possible causes and next treatment steps:

CGVHD can share some symptoms/signs of aGVHD, including erythematous skin rash, nausea, vomiting, diarrhea, and cholestatic liver disease (e.g., the overlap syndrome).

The characteristic signs/symptoms include different organ systems, including skin (lichenoid or sclerotic skin changes), pulmonary (obstructive bronchiolitis), lacrimal and salivary glands (Sicca syndrome [dry eyes and dry mouth]). Esophageal dysmotility, fasciitis and cutaneous sclerosis are uniquely associated with cGVHD.

  • Skin and nail changes

- Poikiloderma, lichen planus, dermal sclerosis, morphea, hypo- or hyper-pigmentation, ichthyosis, nail dystrophy, and onycholysis.

  • Ocular

- Conjunctivitis and corneal ulcerations in severe cases.

  • Pulmonary

- Bronchiolitis obliterans.

  • Loss or decrease of joint flexibility

- This is common, due to fasciitis and other connective tissue changes around the joints.

CGVHD may also cause esophageal dysmotility and strictures, exocrine pancreatic insufficiency, fasciitis (can be eosinophilic fasciitis), arthropathy, oral changes (lichen planus, white patches, hyperkeratotic plaques, mucosal atrophy, mucoceles, fibrosis, ulcers, restricted oral range of motion, and rarely, squamous cell carcinoma), vaginal stenosis or scarring, sexual dysfunction, and autoimmune manifestations.

CGVHD is associated with profound immune dysfunction, including hypogammaglobulinemia, impaired cellular immunity, and functional asplenia.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

  • Complete blood count (CBC)

- CBC with differentiation may reveal thrombocytopenia that is associated with poor prognosis. Eosinophilia can be detected.

  • Complete metabolic panel

- This may reveal cholestatic liver dysfunction, hypoalbuminemia (malabsorption, nephrotic syndrome secondary to glomerulopathy associated with cGVHD), and renal dysfunction (secondary to cGVHD or calcineurin inhibitors [CNIs]).

  • Immunoglobulin levels to assess immune function

  • Schirmer test to evaluate dry eyes

  • Bone marrow aspirate/biopsy

- To exclude other causes of cytopenias (particularly relapse).

  • GastrointestinaI (GI) tract endoscopic evaluations

- These are needed patients with persistent weight loss, decreased appetite, dysphagia, diarrhea. GI biopsies are also useful to rule out opportunistic infections.

  • Pulmonary function tests are critical to evaluate bronchiolitis obliterans

  • Computed tomography (CT) scan

- CT scan of the chest/abdomen/pelvis to evaluate respiratory infections in patients on long-term immunosuppressive drugs for opportunistic infections. Inspiratory/expiratory CT may demonstrate air trapping or peribronchiolar edema or fibrosis.

  • Imaging of the joints

- Appropriate imaging of the joints with inflammatory symptoms and arthrocentesis if there is adequate fluid, to exclude infectious process should be considered.

What conditions can underlie chronic graft-versus-host disease after bone marrow transplant:

The first step is to make a diagnosis whether symptoms/signs are indicative of classical cGVHD, overlap syndrome or late aGVHD, which will affect treatment.

Thrombocytopenia: Consider other causes, including autoimmune thrombocytopenia, transplant-associated thrombotic microangiopathy (TMA), hypersplenism, or relapse.

Steroid-induced myopathy can be difficult to distinguish as a cause of weakness and fatigue. In these patients, electroneuromyography and deep muscle biopsies may be needed, particularly if myositis is present.

When do you need to get more aggressive tests:

  • Tissue biopsies

- Tissue biopsies may be needed for diagnosis of cGVHD.

  • Skin

- Lichen-planus like (combination of epidermal orthokeratosis, hypergranulosis, and acanthosis with lichenoid changes ± syringitis of eccrine units ± panniculitis).

  • Skin sclerotic

- Collagenous deposition with thickening throughout the papillary dermis, or pan-dermal collagenosis ± panniculitis.

  • Skin morphea

- Clinically focal or localized lesion, predominated by sclerosis in the lower reticular dermis or along the dermal-hypodermal border ± epidermal and appendigeal involvement.

  • Oral Changes

- Lymphocytic infiltration of the salivary gland ducts, individual ductal epithelial cell necrosis, and destruction of acinar tissues with periductal fibrosis. Dense fibrosis and acinar destruction most probably reflects past disease, whereas fibroplasia, acinar and periductal inflammation and ductal damage most probably indicate active GVHD.

  • Liver

- Although not specific, ductopenia, portal fibrosis, and chronic cholestasis can be observed.

  • GI tract

- Although not specific, ulceration, or submucosal fibrosis can be observed.

What imaging studies (if any) will be helpful?

CT chest (high resolution): may demonstrate air trapping with BO.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?


Mild cGVHD

Only topical immunosuppression (for example, topical steroids, topical photochemotherapy/phototherapy [PUVA/UVB], CNIs etcetera) is recommended. Mild liver dysfunction or fasciitis may be treated with steroids alone. Ursodiol can be added in liver cGVHD.

Moderate to Severe cGVHD

Although treatment of cGHVD is usually less aggressive than that of aGVHD, it must be longer.

Major components of cGVHD treatment

Major components of cGVHD treatment comprise immunosuppressive therapy, specific infection prophylaxis (antimicrobiological drugs and intravenous immunoglobin [IVIG], and important supportive care (for example, nutritional support, physical therapy, and aggressive management of the polypharmacy accompanying its treatment).

Immunosuppressive therapy is mostly composed of combinations of systemic corticosteroids (prednisone 1mg/kg/day for 2 weeks, then slowly taper to 10 to 20% per month) and calcineurin inhibitors (although results are controversial). In severe patients, whether the addition of a non-CNI agent (for example, mycophenolate mofetil [MMF], mTOR inhibitors (sirolimus), or extracorporeal photopheresis (ECP) may improve the outcome.

In a randomized trial, MMF in addition to initial cGVHD treatment, did not improve responses or survival. Thalidomide when added to other therapy was too toxic and did not improve cGVHD response. In another randomized trial (presented at Tandem meetings, 2016) prednisone along with sirolimus was as effective (and possibly less toxic) as prednisone + CNI + sirolimus.

What other therapies are helpful for reducing complications?


Prospective or retrospective studies demonstrate that addition of anti-T-cell antibodies into GVHD prophylaxis reduces the incidence of cGVHD. However, there is a controversy on whether relapse rate and non-relapse mortality increase with anti-T-cell antibodies.

Steroids addition to GVHD prophylaxis failed to decrease cGVHD incidence in randomized trials. Likewise, MMF or sirolimus additions to GVHD prophylaxis, did not make significant reduction in cGVHD.

What should you tell the patient and the family about prognosis?

Prognosis is worse in patients with severe cGVHD, compared to mild to moderate cGVHD, extensive skin involvement, thrombocytopenia at diagnosis, progressive onset of chronic following acute GVHD. Multiorgan involvement and involvement of the lung or GI tract has a poor prognosis.

Overall survival is quite low (40-50%) in patients with high risk features. In patients with standard risk, the survival rate is better (70-80%). In a recent study, the probability of being alive was high (85% at 10 years) in 2 year survivors of allo-HCT. In these patients, cGVHD and older age were the main causes of mortality observed after 2 years post transplant. Moreover, cGVHD will contribute to poor QOL in surviving patients with cGVHD.

“What if” scenarios.

In salvage therapy, several drugs, such as sirolimus, bortezomib, mycophenolate, ECP, rituximab, imatinib, ruxolitinib, hydroxychloroquine, vitamin A analogs, clofazimine, methotrexate, cyclophosphamide, pentostatin, alemtuzumab, daclizumab, and etanercept have also been evaluated.



CGVHD is primarily resulted from alloreactive T-cells recognizing major and minor histocompatibility antigens (mHAs), as well as non-polymorphic antigens expressed by both the donor and recipient.

Regulatory T-cell dysfunction or deficiency has been observed in patients with cGVHD.

The humoral immune system also contributes to cGHVD pathogenesis. CGVHD patients have various autoimmune antibodies detectable in their sera and clinical symptoms/findings mimic autoimmune disorders such as scleroderma and Sjogren’s syndrome.

What’s the Evidence?

Weisdorf, D.. "Graft vs. host disease: pathology, prophylaxis and therapy: GVHD overview". Best Pract Res Clin Haematol.. vol. 21. 2008. pp. 99-100.

(Reviews the pathogenesis and treatment of aGVHD and cGVHD.)

Socié, G, Schmoor, C, Bethge, WA. "Chronic graft-versus-host disease: long-term results from a randomized trial on GVHD prophylaxis with or without anti-T-cell globulin ATG-Fresenius". Blood.. vol. 117. 2011. pp. 6375-6382.

(Demonstrates that the addition of ATG (anti-thymocyte globulin) to GVHD prophylaxis reduced cGVHD rate without increase in mortality in a prospective study.)

Soiffer, RJ, LeRademacher, J, Ho, V. "Impact of immune modulation with anti-T cell antibodies on outcome of reduced intensity allogeneic hematopoietic cell transplantation for hematologic malignancies". Blood.. vol. 117. 2011. pp. 6963-6970.

(Demonstrates the addition of anti-T cell antibodies to GVHD prophylaxis reduced cGVHD rate but increased relapsed rate in a retrospective study.)

Cutler, C, Kim, HT, Hochberg, E, Ho, V, Alyea, E, Lee, SJ, Fisher, DC, Miklos, D, Levin, J, Sonis, S, Soiffer, RJ, Antin, JH.. "Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation". Biol Blood Marrow Transplant. vol. 10. 2004. pp. 328-36.

(Demonstrates efficacy of a combination of sirolimus and tacrolimus; however no significant reduction in the incidence of cGVHD.)

Neumann, F, Graef, T, Tapprich, C. "Cyclosporine A and mycophenolate mofetil vs cyclosporine A and methotrexate for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings". Bone Marrow Transplant.. vol. 35. 2005. pp. 1089-93.

(Demonstrates the addition of MMF does not reduce cGVHD incidence.)

Flowers, ME, Parker, PM, Johnston, LJ. "Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial". Blood.. vol. 100. 2002. pp. 415-9.

(This study demonstrates that allogenic peripheral blood stem cell transplantation compared to bone marrow transplantation is associated with higher frequency of cGVHD.)

Friedrichs, B, Tichelli, A, Bacigalupo, A. "Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial". Lancet Oncol.. vol. 11. 2010. pp. 331-8.

(Demonstrates that allo-PSCT HCT is associated with higher cGVHD compared to allo-BMT [bone marrow transplant].)

Filipovich, AH, Weisdorf, D, Pavletic, S. "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.. vol. 11. 2005. pp. 945-56.

(A consensus to standardize the criteria for diagnosis of cGVHD with a new clinical scoring system [0 to 3] and new guidelines for global assessment of cGVHD severity.)

Shulman, HM, Kleiner, D, Lee, SJ. "Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report". Biol Blood Marrow Transplant.. vol. 12. 2006. pp. 31-47.

(Consensus on histopathological findings of cGVHD in various organs.)

Martin, PJ, Storer, BE, Rowley, SD. "Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease". Blood.. vol. 113. 2009. pp. 5074-82.

(Demonstrates the efficacy of MMF in cGVHD as a first line agent.)

Koc, S, Leisenring, W, Flowers, ME. "Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone". Blood.. vol. 100. 2002. pp. 48-51.

(Demonstrates that steroids alone is as effective as a combination of steroids and a CNI.)

Sullivan, KM, Witherspoon, RP, Storb, R. "Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease". Blood.. vol. 72. 1988. pp. 555-561.

(Demonstrates the favourable results from a CNI and steroids in treatment of cGVHD.)

Arora, M, Wagner, JE, Davies, SM. "Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease". Biol Blood Marrow Transplant.. vol. 7. 2001. pp. 265-73.

(A randomized trial showing no improvement in cGVHD by addition of thalidomide.)

Jagasia, MH, Greinix, HT, Arora, M, Williams, KM, Wolff, D, Cowen, EW. "National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report". Biol Blood Marrow Transplant. vol. 21. 2015 Mar. pp. 389-401.

(Describes national guidelines for clinical trials focusing on cGVHD.)

Pidala, J, Chai, X, Kurland, BF, Inamoto, Y, Flowers, ME, Palmer, J. "Analysis of gastrointestinal and hepatic chronic graft-versus-host [corrected] disease manifestations on major outcomes: a chronic graft-versus-host [corrected] disease consortium study". Biol Blood Marrow Transplant.. vol. 19. 2013 May. pp. 784-91.

(Describes liver related complications and their outcomes.)

Arora, M, Klein, JP, Weisdorf, DJ, Hassebroek, A, Flowers, ME, Cutler, CS, Urbano-Ispizua, A. "Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis". Blood.. vol. 117. 2011 Jun 16. pp. 6714-20.

(Describes cGVHD prognostic risk scoring per CIBMTR.)

Magenau, J, Runaas, L, Reddy, P.. "Advances in understanding the pathogenesis of graft-versus-host disease". Br J Haematol.. vol. 173. 2016 Apr. pp. 190-205.

(This review discuss recent progression in GVHD pathogenesis.)
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