Treatment of Chronic Steroid-Refractory Graft-Versus-Host... : Transplantation (original) (raw)
Despite the improvement of allogeneic hematopoetic stem-cell transplantation (HCT) since its introduction in the therapy of hematologic malignancies more than 50 years ago, chronic graft-versus-host disease (cGvHD) still remains a debilitating complication associated with high morbidity and considerable mortality. In the past, the pathophysiology of cGvHD has been mainly attributed to dysregulation of donor T cells by host antigen-presenting cells (1–2); therefore, beside corticosteroids, pharmacologic therapy has been focused on T-cell inhibition. Recently, a potential role of B-cell activation and antibody-mediated tissue damage in cGvHD has become obvious (1–6) and consequently rituximab, an anti-CD20 chimeric monoclonal antibody, has been tested in this indication. In most reports, rituximab (375 mg/m2 per week) was effective in more than 50% of heavily pretreated patients with steroid-refractory cGvHD (7–10). The dosage of 375 mg/m2 weekly was originally developed for the treatment of B-cell non-Hodgkin-lymphoma, but in non-malignant disorders, the target cell population is probably smaller than in CD20+ lymphoma. In fact, a recent study with low-dose rituximab (100 mg fixed dose weekly) for autoimmune cytopenias achieved a significant and durable response in these patients (11). Especially in patients with cGvHD receiving several immunosuppressive drugs, dose-reduction without loss of efficacy is desirable to reduce potential side effects and treatment costs.
In this report, we describe the course of 13 patients with steroid-refractory cGvHD receiving low-dose rituximab (50 mg/m2). The patients’ characteristics are summarized in Table 1.
Patients’ characteristics
Median age at transplantation was 60 years (range, 40-67 years). All patients received peripheral blood stem cells (eight from a sibling donor and five from an unrelated donor) after varying conditioning regimes because of different hematologic malignancies. Four patients had received grafts from a human leukocyte antigen-mismatched donor.
Staging and grading of cGvHD was performed according to the National Institutes of Health consensus criteria (12, 13). All patients had failed to respond to at least two immunosuppressive regimes, including corticosteroids plus a calcineurin inhibitor, the most common agents used for treatment. The skin and mouth were the most frequent sites of cGvHD manifestations, affecting nine and eight patients, respectively. Other organs involved were as follows: eyes (four patients), muscles (four patients), liver (three patients), lung (two patients), and gastrointestinal tract (two patients). Two patients developed autoimmune disorders after allogeneic HCT: one with histologically proven membranous gomerulonephritis and one with immune thrombocytopenic purpura with detection of specific autoantibodies directed against platelet membrane glycoproteins. Because all immunosuppressive agents so far had failed to relieve symptoms of cGvHD or autoimmune disease, these patients received off-label rituximab after providing written informed consent. Low-dose rituximab was administered at a weekly dose of 50 mg/m2. All patients received acetaminophen, H1/H2 receptor antagonists, and 50 mg prednisolone before rituximab application. Global response criteria were defined as follows: progressive disease (PD) in cases of increase in staging or number of affected organs, no response (NR)in cases of no changes in staging or organ involvement, mixed response (MR) in cases of improvement in staging of one organ with no change in others, partial response (PR) in cases of decrease in staging but no resolution of all signs, complete response (CR) in cases of resolution of all signs, and overall response (OR) included CR, PR, and MR.
Peripheral blood samples were collected in EDTA-tubes for subsequent fluorescence-activated cell sorting of B cells (CD19+), natural killer cells (CD56+/CD16+/CD3−), T cells (CD3+), T-helper-cells (CD4+), and cytotoxic-cells (CD8+). Standard staining and analysis protocols were applied using commercial fluorescein isothiocyanate or phycoerythrin-conjugated antibodies (Becton Dickinson, San Jose, CA). The analysis of the lymphocyte subsets was performed before and after rituximab infusion.
Course of therapy and response are summarized in Table 2. Median time from transplantation to first rituximab infusion was 651 days (range, 267-1815 days).
Patients’ response to rituximab
The first nine patients, including the two with autoimmune disorders, received four cycles of low-dose rituximab. In patients suffering from cGvHD, the OR (CR, PR, and MR) was 33%, including one CR. NR and PD was observed in three and one patient, respectively.
The first nine patients received four cycles of low-dose rituximab afterward, irrespective of the response. Because the response in those patients with cGvHD occurred no later than the second rituximab infusion and showed no further amelioration afterward, we decided to adapt the number of administrations to the clinical course in the following cases: maximally, four cycles were given, and if a response occurred, the rituximab infusion was stopped earlier. Using this approach, the most frequent number of cycles was two. All subsequent patients responded to therapy.
At the time of diagnosis of membranous gomerulonephritis, patient 8 was without any immunosuppressive medication. Under a combination of cyclosporine A (CsA) and prednisolone, the proteinuria worsened (data not shown). On day 751 after transplantation, in addition to the existing immunosuppressive therapy with CsA and prednisolone, the first cycle of rituximab infusion was administered, but proteinuria persisted. However, despite tapering of the prednisolone, proteinuria decreased after the fourth administration of rituximab but did not reach normal values (Fig. 1A). In the patient with immune thrombocytopenic purpura (patient 9), even after the first rituximab administration, platelet counts began to increase and returned to baseline values after two cycles of rituximab (Fig. 1B). The patient is currently free of immunosuppressive therapy and no specific autoantibodies are detectable anymore. The final rate of OR was 69% (n=9). Three patients achieved CR (23%); two and four patients fulfilled PR (15%) and MR (30%) criteria, respectively. Improvement (CR and PR) in skin, mouth, and muscle involvement was observed in 5 (55%), 4 (50%), and 3 (75%) cases, respectively. No improvement could be seen in cGvHD of the eyes, gastrointestinal tract, liver, or lungs. Three patients did not respond to the therapy, and only one patient showed PD.
Patients with autoimmune disorders after HCT. (A) Patient 8, with membranous glomerulonephritis. (B) Patient 9, with immune thrombocytopenic purpura.
All patients who achieved CR are currently without immunosuppressive therapy. In cases of PR, the subjects still receive immunosuppression (mycophenolic acid or CsA), but corticosteroids could be tapered off. At this time, all patients with MR are treated with corticosteroid-containing regimens; however, in two patients, the corticosteroid dose could be diminished.
All infusions were tolerated well under the prophylaxis mentioned above. Two patients developed infectious complications within 6 months after the last rituximab administration and one died because of pneumonia.
Even after the first rituximab infusion, the fluorescence activated cell sorting analyses showed a complete disappearance of peripheral blood B cells independent of response, whereas natural killer and T cells did not show significant changes (data not shown).
Apart from relapse of the underlying malignancy, cGvHD remains the main reason for morbidity and decreased quality of life in patients after allogeneic HCT. Despite increased understanding of the pathophysiology of cGvHD, therapeutic algorithms have still not been standardized, and success is often unpredictable. Most immunosuppressive regimes are associated with considerable adverse effects. Several new therapeutic strategies have been introduced for cGvHD: pharmacological regimes with corticosteroids, calcineurin inhibitors, and alternative treatments (e.g., pentostatine, mycophenolate mofetil, daclizumab, and etanercept); immunomodulating procedures (e.g., extracorporeal photopheresis, psoralen, and ultraviolet irradiation); and T-cell-depleting antibodies (e.g., Alemtuzumab) (1–3). Recently, the role of B cells has become evident not only in autoimmune disorders but also in the pathogenesis of cGvHD. In some studies, circulating autoantibodies could be observed and were associated with different forms and activity of cGvHD (6, 7). Consequently, rituximab at a standard weekly dose of 375 mg/m2 has been introduced in the therapy of cGvHD and has shown promising activity, even in heavily pretreated patients (7–10). Because patients after allogeneic stem-cell transplantation often have B-lymphocytopenias, we administered low-dose rituximab (50 mg/m2) for steroid-refractory cGvHD. Despite dose reduction, a significant and durable response could still be observed (11). Even with low-dosage and areduced number of administrations, we observed similar response rates (including 23% CR) as reported earlier (7–10). Consistent with recent studies, cutaneous and oral cavity lesions and musculoskeletal symptoms responded especially well to therapy (7–10). Interestingly, in our series, a response occurred even after the first or second rituximab cycle and plateaued, despite consecutive rituximab application. Additionally, despite dose reduction, a nearly complete depletion of B cells in the peripheral blood could be observed after the first dose but was not linked to clinical response (data not shown). Also, the initial B-cell count did not seem to predict the response to rituximab (data not shown).
In conclusion, these data confirm the clinical activity of rituximab in severe and moderate cGvHD, even when given at lower doses. Further prospective controlled studies are needed to evaluate the optimal schedule and dosage of an anti-CD20 antigen targeted-therapy of cGvHD.
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Keywords:
Allogeneic hematopoetic stem-cell transplantation; Chronic graft-versus-host disease; Low-dose rituximab
© 2008 Lippincott Williams & Wilkins, Inc.