Graft-versus-host disease Clinical importance of confirming or ... - Nature

Bone Marrow Transplantation (2001) 28, 1047–1051  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Graft-versus-host disease Clinical importance of confirming or excluding the diagnosis of chronic graft-versus-host disease DA Jacobsohn1, S Montross2, V Anders2 and GB Vogelsang2 1

Department of Oncology and Pediatrics, Hematologic Malignancies, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; and 2Department of Oncology, Division of Hematologic Malignancies, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Summary: Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation. The presentation of this disease is varied, and it requires histological confirmation for diagnosis. In addition, cGVHD can often mimic other diseases, and vice versa. We have conducted a retrospective analysis of 123 patients referred to the GVHD clinic at the Johns Hopkins Oncology Center from 1994 to 1998 with a diagnosis of active cGVHD. Of these, nine patients (7%) had no evidence of cGVHD, and 25 patients (20%) had inactive cGVHD. Many of these patients were found to have other processes accounting for their ongoing symptoms. We conclude that since the therapy for this disease has significant toxicities and since what appears to represent cGVHD may actually be another disease, correct diagnosis of cGVHD or exclusion of this diagnosis is essential. Bone Marrow Transplantation (2001) 28, 1047–1051. Keywords: chronic GVHD; diagnosis; hematopoietic cell transplantation

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). cGVHD occurs in 27–50% of siblingmatched bone marrow transplants (BMT),1–3 47–72% of unrelated BMTs,4,5 and 38–77% of G-CSF-stimulated allogeneic peripheral blood stem cell transplants.6–8 It can lead to major disability, opportunistic infections, and even death in some patients.9–11 Whereas acute GVHD is a distinctive syndrome with stereotypical involvement of the skin, gastrointestinal tract and liver, cGVHD is much more diverse in its symptomatology. It can affect almost any organ in the body, and it often mimics autoimmune diseases such as Sjo¨gren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, and scleroderma.12,13 Although the most common sites of Correspondence: Dr DA Jacobsohn, Johns Hopkins Hospital, Pediatric Oncology/CMSC 800, 600 North Wolfe Street, Baltimore, MD 21287, USA Received 10 January 2001; accepted 25 July 2001

involvement are the skin, mouth, liver, eyes, esophagus, and upper respiratory tract, cGVHD can also affect the small intestine, lungs, muscle and serous surfaces.11 Given the extremely varied presentation of cGVHD, histological confirmation is necessary for its diagnosis.14 The treatment of cGVHD can also lead to significant morbidity. For example, potent immunosuppressive agents such as corticosteroids, cyclosporine, and tacrolimus (FK506) increase the risk of opportunistic infections. Corticosteroids also have additional significant complications, such as steroid-induced diabetes and avascular necrosis.15 Cyclosporine and FK506 can be associated with severe renal toxicity and electrolyte abnormalities.16 When used in combination, these agents present even greater risks and side-effects. To our knowledge, there has been no published information regarding the correlation between cGVHD diagnosis by a primary oncologist or transplant center and its diagnosis or confirmation at a tertiary care center’s GVHD clinic. Such data would be of interest since they could shed light on the importance of confirming the diagnosis of cGVHD diagnosis before beginning potent immunosuppressive therapy. In addition, given the number of multicenter trials dealing with therapy for cGVHD and trials of allogeneic HCT in which cGVHD is an endpoint, such data could help the medical community assess the reliability of cGVHD diagnosis among different physicians. We now report the results of a retrospective analysis involving all patients who were referred between 1994 and 1998 to our multidisciplinary GVHD clinic with a diagnosis of active cGVHD and were receiving ongoing immunosuppressive therapy. We have found that more than 25% of the patients referred with this diagnosis either had no evidence of cGVHD or had no evidence of ongoing, active cGVHD. Patients and methods In 1994, a multidisciplinary GVHD clinic was established at the Johns Hopkins Oncology Center. This clinic’s treatment recommendations focus not only on specific therapy for GVHD, but also on rehabilitation and nutritional and psychosocial problems. This study is a retrospective analysis of all 123 patients referred to this GVHD clinic between

Diagnosis of cGVHD DA Jacobsohn et al

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1994 and 1998 with a diagnosis of active cGVHD. The main objective of the analysis was to collect data regarding the numbers of patients who were being treated for active cGVHD, but really had inactive cGVHD or had no evidence of cGVHD. Given the diversity of immunosuppressive regimens the patients were on, the study was incapable of examining the effectiveness of individual treatment regimens and therefore the data was not analyzed as such. Study definitions Diagnosis of cGVHD: Diagnosis of cGVHD by our clinic was made on the basis of both clinical and histologic criteria for the skin and other affected sites, as previously described.12,17,18 The histologic diagnosis was made using established criteria.18,19 Patients brought slides of a biopsy of the affected organ, or a biopsy was performed at our institution. All samples were examined by pathologists at the Johns Hopkins Hospital. Months of therapy for cGVHD: Months of therapy for cGVHD was defined as the number of months that had elapsed between the time the patient was diagnosed with cGVHD and started on therapy by the referring physician and the date that the patient was first seen at our clinic.

Table 1

Patient characteristics

No. of patients Age at visit, years Median Range Gender History of acute GVHD Type of bone marrow transplant Matched-sibling donor Matched-unrelated donor 1-antigen mismatched donor 2-antigen mismatched donor Matched-sibling PBSC Matched-sibling, followed by DLI Matched-sibling, followed by PBSC Autologous, followed by matched sibling Indication for bone marrow transplant Chronic myelogenous leukemia Acute myelogenous leukemia Acute lymphoblastic leukemia Aplastic anemia Myelodysplastic syndrome Multiple myeloma Non-Hodgkin’s lymphoma Hodgkin’s disease Paroxysmal nocturnal hemoglobinuria Biphenotypic leukemia Chronic lymphocytic leukemia Fanconi’s anemia Hurler’s syndrome Juvenile chronic myelogenous leukemia

123 34 2–64 56F/67M 81/123 70 30 12 2 2 4 1 2 45 27 14 10 6 5 5 2 2 2 2 1 1 1

Active cGVHD: Patients were identified as having active disease if they had a biopsy confirming cGVHD and had evidence of progressive or persistent disease over the past 3–6 months (based on the patient’s and referring physician’s reports).

PBSC = peripheral blood stem cell transplant; DLI = donor lymphocyte infusion.

No cGVHD: Patients were considered to have no cGVHD if they had negative biopsies for all organs ever suspected of having cGVHD.

Eighty-nine patients had a diagnosis of active cGVHD confirmed. Out of these, 61 (69%) had sclerodermatous skin involvement, 13 (15%) had lichenoid skin involvement, 45 (50%) had fascial involvement, 17 (19%) had musculoskeletal involvement, four (4%) had gastrointestinal involvement, 39 (44%) had oral cGVHD, four (4%) had lung cGVHD, six (7%) had liver cGVHD, and 25 (28%) had ocular cGVHD.

Inactive cGVHD: Patients were identified as having inactive disease if they had a biopsy showing cGVHD, but their disease had been completely stable over the past 3–6 months. A period of 3–6 months was chosen because we had previously observed at our institution that the majority of patients who have had no improvement (as well as no progression) do not improve if further maintained on immunosuppressive therapy.20 Follow-up was obtained on all patients in whom immunosuppressive therapy was stopped.

Results A total of 123 patients were referred to the Johns Hopkins Oncology GVHD clinic between 1994 and 1998 with a diagnosis of active cGVHD (Table 1). The diagnosis was confirmed in 89 (72%) of the patients. Biopsies, physicians’ reports, patient interviews, and phyisical examinations were used to confirm or exclude the diagnoses. In nine (7%) patients the diagnosis of cGVHD was excluded and in 25 (20%) patients the diagnosis of inactive cGVHD was made. Bone Marrow Transplantation

Patients whose diagnosis of active cGVHD was confirmed

Patients diagnosed as having no cGVHD The nine patients who we identified as having no cGVHD had been treated for a median of 11 (range 2–36) months before consultation in our clinic. The prior immunosuppressive therapy and major symptoms of each patient are outlined in Table 2. None of these patients had undergone a biopsy before starting immunosuppressive therapy. A biopsy was obtained by our clinic from each of these nine patients and all showed no histological evidence of cGVHD. The main recommendation for all of these patients was tapering of their immunosuppressive therapy. Patients with other suspected diagnoses were referred for appropriate evaluation. Six of the nine patients were further diagnosed with non-cGVHD-related processes that accounted for their ongoing symptoms (Table 2). One patient in this group died. This patient presented to


Table 2 Patient 1 2 3 4 5 6 7 8 9

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Symptoms, alternate diagnoses, and prior therapies for patients diagnosed as having no cGVHD Symptoms arthralgias, non-specific dermatitis dyspnea, wheezing alopecia, seborrheic dermatitis dysphagia erythroderma diarrhea non-specific dermatitis non-specific dermatitis vesicular rash

Alternate diagnosisa myasthenia gravis reactive airway disease esophageal stricture erythrodermic psoriasis eczema zoster

Therapyb CsA (1), oral steroid (1)c oral steroid (6) steroid cream (12) CsA (20), oral steroid (8) CsA (6), oral steroid (11) CsA (3), oral steroid (3) CsA (6), steroid mouth rinse (1) CsA (14), oral steroids (14) oral steroid (1)

a

Specified when an alternate diagnosis was confirmed by the appropriate specialist. Followed by months having undergone particular therapy prior to referral, in parenthesis. c Only therapeutic doses of steroids are included. CsA = cyclosporin A. b

his primary oncologist with a disseminated vesicular rash that was mistaken for worsening cGVHD and was treated with immunosuppressive therapy. During his visit to our institution he was found to have disseminated herpes zoster with blistering lesions and he died of herpes encephalitis despite aggressive therapy. Of the eight patients that remained alive in this group, two have subsequently developed biopsy-proven cGVHD (median follow-up 17 months). These patients were placed on alternate immunosuppressive therapy. Patients diagnosed as having inactive cGVHD The 25 patients we diagnosed as having inactive cGVHD had been treated for a median of 23 (range 3–85) months before referral to our clinic. The main cGVHD symptoms and prior immunosuppressive therapy for each patient are detailed in Table 3. All of these 25 patients were considered to have inactive cGVHD because there was clear evidence of stability in the disease for at least the last 3–6 months before referral. Patients felt there had been no improvement in their symptoms during this period, and examinations conducted by their referring physicians confirmed stability. By clinical criteria, the majority of these patients had sclerodermatous cGVHD, many with fixed contractures. The main recommendation for most of these patients was to taper their immunosuppressive therapy since there was no clinical evidence of ongoing cGVHD. Patients with other suspected diagnoses were referred for appropriate evaluation. Seven of these patients were diagnosed with non-cGVHD-related processes that in most accounted for their ongoing symptoms (Table 3). Of the 25 patients in this group, seven developed active cGVHD again (median follow-up, 17 months) and needed to restart alternate immunosuppressive therapy. Discussion In this study, we have examined the correlation between a diagnosis of active cGVHD by the patients’ physicians and its diagnosis or confirmation at our tertiary care center’s GVHD clinic. Our observations indicate that some patients

are diagnosed with active cGVHD and are started on immunosuppressive agents in the absence of a biopsy confirming the disease. Some of these patients are maintained on therapy for an extended period of time. In our study, almost 10% of the patients referred to our clinic with a diagnosis of active cGVHD had no evidence of cGVHD and, in fact, had other diseases accounting for their symptoms. For example, one patient referred for worsening cGVHD with new blistering lesions was found to have disseminated zoster and died of herpes encephalitis. In our experience, more specific approaches to the presenting problem often result in improvement of the symptoms. For example, one patient with severe dyspnea and erythroderma was found to have atopic dermatitis and severe allergies. Specific therapy for these problems has significantly improved his clinical symptoms. However, this and similar patients will require close monitoring. We have previously reported that patients with skin damage may develop GVHD in the distribution of their skin damage. Patients with extensive skin damage may express target antigens for GVHD and certainly have increased cytokine levels from their ongoing organ damage.21 Both of these may contribute to an increased risk for GVHD. These factors may also explain why about 25% of the patients who were tapered off immunosuppressive therapy either developed cGVHD or reverted to active cGVHD. The patients in whom therapy is tapered are followed very closely by our clinic and are started on immunosuppressive therapy as soon as they show signs of active cGVHD given the increased risk of infective death in patients with cGVHD not on therapy.9,10 Furthermore, we recently described22 four patients who had severe diarrhea which had been attributed to cGVHD and who had been prescribed immunosuppressive medications. However, this therapy did not improve their symptoms. When seen in our clinic, these patients were diagnosed with pancreatic insufficiency, and their diarrhea improved once they began receiving pancreatic enzymes. Our data also suggest that an appreciable number of patients are correctly diagnosed with cGVHD but are kept on immunosuppressive therapy for a prolonged period of time despite a lack of continued improvement in their symptoms. Given the clinical information, we would label these patients’ cGVHD as inactive, even if a current biopsy Bone Marrow Transplantation


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Table 3 Patient

CGVHD mainfestations, additional diagnoses and prior therapies for patients diagnosed as having inactive cGVHD Main cGVHD manifestations

1

Scleroderma

2 3

Fasciitis Scleroderma, fasciitis

4 5 6 7 8

Scleroderma, fasciitis Scleroderma Scleroderma Scleroderma Scleroderma

9 10

Scleroderma, musculoskeletal Scleroderma

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Oral Oral, gastrointestinal Scleroderma Scleroderma Scleroderma Scleroderma Lichenoid skin, oral, ocular Ocular Oral Lichenoid skin, oral Scleroderma, musculoskeletal Scleroderma Scleroderma Gastrointestinal Scleroderma

Additional diagnosisa

Drug allergy

HUS/TTP

Depression Bronchiectasis Corneal infiltrate

Reactive airway disease Hepatitis C

Therapyb CsA (32), oral steroidc (40), azathioprine (6), PUVA (4), FK506 (2) CsA (9), oral steroid (8), azathioprine (11), etretinate (4) CsA (34), oral steroid (34), PUVA, FK506 (9), clofazamine (4) oral steroid (30), PUVA oral steroid (19), azathioprine (7) oral steroid (10), azathioprine (8) CsA (4), thalidomide (2), FK506 (1) CsA (52), oral steroids (16), azathioprine (12), thalidomide (3) CsA (17), oral steroid (17), azathioprine (1) CsA (9), oral steroid (9), azathioprine (unknown), plaquenil (unknown), FK506 (1) CsA (4), oral steroid (10) CsA (16), oral steroid (59), clofazamine (3) CsA (4), oral steroid (5), azathioprine (4) CsA (4), oral steroid (36), PUVA CSA (24), oral steroid (24) CsA (4), oral steroid (1), PUVA CsA (26), oral steroid (25), azathioprine (24) oral steroid (29), mycophenolate mofetil (1) CsA (3), oral steroid (3), steroid mouth rinse (3) CsA (8), oral steroid (7) CsA (20), oral steroid (2) CsA (14), oral steroid (14), plaquenil (13) CsA (22), oral steroid (22) oral steroid (48), azathioprine (9) CsA (57), azathioprine (57)

a

Specified when clinic visit prompted an additional diagnosis for the particular patient Followed by months having undergone particular therapy, in parenthesis Only therapeutic doses of steroids are included. CsA = cyclosporin A; PUVA = psoralen and ultraviolet A irradiation; FK506 = tacrolimus.

b c

showed continued sclerotic changes. In particular, we saw a number of patients with joint immobility who were taking immunosuppressive medication for months to years, but had had no change in symptoms for months. There are no data to suggest that these patients are getting benefit from their continued therapy. In fact, these patients may simply be accumulating the therapy’s toxicity and potential complications. In reviewing 85 patients treated for cGVHD at Johns Hopkins Hospital, we found that patients who had not improved by 3 months on a particular regimen did not respond to continued therapy with the same medications.20 Our study has several limitations. First of all, this analysis is retrospective in nature. Therefore, it could potentially be subject to misclassification bias in terms of cGVHD categories. This is unlikely because patients were categorized at the time of their visit. We use stringent criteria based on clinical and histologic information to categorize a patient into active, inactive or no cGVHD. We still realize that it is necessary to validate our cGVHD categories in a prospective study. Because our patients’ characteristics were quite representative of the typical types of and indications for transplants, we suggest that the results of this analysis may be generalized to other HCT populations. We conclude that it is extremely important to establish a diagnosis of cGVHD before treatment is begun. Our study indicates that overdiagnosing cGVHD can lead not only to Bone Marrow Transplantation

unnecessary potentially toxic therapies but also to a failure to diagnose other diseases that may actually be responsible for the symptoms. In patients with established cGVHD, it is important to assess a response at reasonable intervals (approximately every 3 months) or whenever the clinical status has changed. Even in patients with proven cGVHD, other conditions can occur that will need treatment. When it is unclear that cGVHD is the cause of the patient’s problems, referral to the initial transplant center or to a transplant center with an interest in late bone marrow transplant complications should be considered.

Acknowledgements The authors thank Deborah McClellan, PhD for her kind suggestions in preparing this manuscript.

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