Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing.

Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304.

Mycophenolate mofetil for remission maintenance in the treatment of Wegener's granulomatosis.

OBJECTIVE: To examine the safety of mycophenolate mofetil (MMF) for remission maintenance in patients with Wegener's granulomatosis (WG) who had been treated with daily cyclophosphamide (CYC) and glucocorticoids to induce remission. METHODS: Fourteen patients were treated for active WG using a standardized regimen of CYC and glucocorticoids for induction of remission and MMF for remission maintenance. Outcome was assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: Remission occurred in all 14 patients (100%) at a median time of 3 months. The median time to discontinuation of glucocorticoids was 8 months. No patients died during protocol treatment and 6 patients (43%) relapsed at a median of 10 months after achieving remission. MMF was well tolerated and no patients had to be withdrawn as a result of medication toxicity. CONCLUSION: The use of CYC and glucocorticoids for induction of remission and MMF for remission maintenance was well tolerated, but disease relapses were observed.

Tarsal-conjunctival disease associated with Wegener's granulomatosis.

OBJECTIVE: To describe the clinical characteristics of tarsal-conjunctival disease in a cohort of patients with Wegener's granulomatosis (WG). DESIGN: Retrospective, case-controlled study. PARTICIPANTS: The medical records of 82 consecutive WG patients who underwent an eye examination between January 1996 and June 2002 at the National Institutes of Health were reviewed. METHODS: Details of the ophthalmic examination, results of medical therapy, and histopathologic analysis results were recorded. Tarsal-conjunctival disease was defined by (1). conjunctival hyperemia and granuloma formation, areas of necrosis, or active fibrovascular changes in the tarsus or conjunctiva, or (2). evidence of inactive fibrovascular scar. The association of tarsal-conjunctival disease with major organ system involvement was assessed using Bayesian methods. MAIN OUTCOME MEASURES: The occurrence and clinical characteristics of tarsal-conjunctival disease in a cohort of patients with WG and associations with major organ system involvement. RESULTS: Tarsal-conjunctival disease occurred in 13 of 82 patients (16%) with WG examined over a 6.5-year period. The palpebral surface of the upper lid was involved most commonly, showing conjunctival hyperemia in seven patients, granulomatous lesions in three patients, tarsal-conjunctival necrosis in four patients, active fibrovascular proliferation in six patients, and inactive fibrous scar tissue in seven patients. Histopathologic analysis of eyelid biopsy specimens showed granulomatous inflammation, focal necrosis, and areas of occlusive vasculitis in the tarsus and conjunctiva. In reviewing the patterns of organ involvement in patients with and without tarsal-conjunctival disease, the association of subglottic stenosis and nasolacrimal duct obstruction with tarsal-conjunctival disease showed a high probability of clinical significance. CONCLUSIONS: Tarsal-conjunctival disease, a previously uncommon finding in patients with WG, was characterized by inflammation of the palpebral conjunctiva and tarsus followed by a fibrovascular proliferation and scar formation. Because of the important association of tarsal-conjunctival disease with subglottic stenosis, which can progress and lead to laryngeal obstruction and respiratory failure, patients with tarsal-conjunctival disease should be referred to an otolaryngologist for evaluation.

Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse.

PURPOSE: To determine the relapse rate and outcome in patients with Wegener's granulomatosis treated with daily cyclophosphamide and glucocorticoids to induce remission followed by methotrexate for remission maintenance. METHODS: We performed an open-label prospective study in 42 patients with active Wegener's granulomatosis. All patients were treated with a standardized regimen. Outcomes were assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: All patients achieved disease remission. The median time to remission was 3 months, and the median time to discontinuation of glucocorticoids was 8 months. During a median of 32 months of follow-up, 1 patient died (of a myocardial infarction not related to vasculitis). Two patients (5%) had to withdraw from the study because of medication toxicity. Twenty-two patients (52%) relapsed, with glomerulonephritis occurring in 16 patients. Of these 16 patients, 4 had an increase of >0.2 mg/dL in serum creatinine level. All 4 patients returned to their prior level of renal function with treatment. None of the 22 relapses met the criteria for severe disease. CONCLUSION: The use of cyclophosphamide and glucocorticoids for induction and methotrexate for maintaining remission is an effective and well-tolerated therapeutic approach in patients with active Wegener's granulomatosis.