Philippe Casassus

Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients.

Churg-Strauss syndrome (CSS) is a systemic vasculitis characterized by the presence of asthma, hypereosinophilia, and necrotizing vasculitis with extravascular eosinophil granulomas. In this retrospective study of 96 patients between 1963 and 1995, we analyzed clinical manifestations, identified prognostic factors, and assessed the long-term outcome. CSS was diagnosed when asthma, hypereosinophilia > 1,500/mm3 or > 10%, and clinical manifestations consistent with systemic vasculitis, with or without histologic evidence, were present. Asthma was the most frequently observed manifestation at presentation, with mononeuritis multiplex the second. Other common manifestations were weight loss, fever, myalgia, skin involvement, paranasal sinusitis, arthralgia, pulmonary infiltrate, and gastrointestinal involvement. Mean eosinophilia at presentation was 7.193 +/- 6.706/mm3; ANCA, present in 20 of 42 (47.6%) patients, predominantly gave the perinuclear labeling pattern. All the patients were treated with corticosteroids alone or in combination with cyclophosphamide or plasma exchanges. Clinical remission was obtained in 91.5%; 22 (25.6%) patients relapsed. Twenty-three patients died during follow-up: 11 of these deaths were directly due to vasculitis. The presence of severe gastrointestinal tract or myocardial involvement was significantly associated with a poor clinical outcome. The long-term prognosis of CSS is good and does not differ from that of polyarteritis nodosa, although most patients need low doses of oral corticosteroids for persistent asthma, even many years after clinical recovery from vasculitis.

Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial

BACKGROUND In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival. METHODS Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126). The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00367185. FINDINGS After a median follow-up of 51.5 months (IQR 34.4-63.2), median overall survival times were 33.2 months (13.8-54.8) for MP, 51.6 months (26.6-not reached) for MPT, and 38.3 months (13.0-61.6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59, 95% CI 0.46-0.81, p=0.0006) or MEL100 regimen (0.69, 0.49-0.96, p=0.027). No difference was seen for MEL100 versus MP (0.86, 0.65-1.15, p=0.32). INTERPRETATION The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should, at present, be the reference treatment for previously untreated elderly patients with multiple myeloma.

PROGNOSTIC FACTORS IN POLYARTERITIS NODOSA AND CHURG-STRAUSS SYNDROME : A PROSPECTIVE STUDY IN 342 PATIENTS

We undertook this study to determine the clinical, biologic, immunologic, and therapeutic factors associated with the prognoses of polyarteritis nodosa (PAN) and Churg-Strauss syndrome (CSS). Three hundred forty-two patients (260 with PAN, 82 with CSS) followed from 1980 to 1993 were included in a prospective study on prognostic factors. Two hundred eighty-eight of these patients were included in the prospective studies on PAN and CSS. Items to be considered for analysis were collected at the time of diagnosis, during the acute phase of the disease. A survival curve was plotted for each clinical and biologic symptom observed in PAN or CSS. Each treatment arm of the prospective therapeutic trials was also tested: 1) prednisone (CS) + oral cyclophosphamide (CYC) + plasma exchanges (PE) versus CS E, 2) CS + PE versus CS, 3) CS + oral CY versus CS + pulse CY, 4) CS + pulse CY + PE versus CS + pulse CY in severe PAN and CSS, and 5) PE + antiviral agents after short-term CS in hepatitis B virus-related PAN. Of the parameters thus evaluated, the following had significant prognostic value and were responsible for higher mortality: proteinuria > 1 g/d (p < 0.0001; relative risk [RR] 3.6), renal insufficiency with serum creatinine > 1.58 mg/DL (p < 0.02; RR 1.86), GI tract involvement (p < 0.008. RR 2.83 for surgery). Cardiomyopathy and CNS involvement were associated with a RR of mortality of 2.18 and 1.76, respectively; these were not statistically significant. Similar survival rates were obtained with the prospectively tested therapies. The five-factors score (FFS) we established considered the prognostic factors creatinemia, proteinuria, cardiomyopathy, GI tract involvement, and CNS signs. Multivariate analysis showed that proteinuria (due to vascular or glomerular disease) and GI tract involvement were independent prognostic factors. When FFS = 0 (none of the 5 prognostic factors present), mortality at 5 years was 11.9%; when FFS = 1 (1 of the 5 factors present), mortality was 25.9% (p < 0.005); when FFS > 2 (3 or more of the 5 factors present), mortality was 45.95% (p < 0.0001 between 0 and 2, p < 0.05 between 1 and 2). We conclude that an initial assessment of PAN or CSS severity enables outcome and mortality to be predicted. The FFS is a good predictor of death and can be used to help the clinician choose the most adequate treatment. Renal and GI signs are the most serious prognostic factors.

Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients.

OBJECTIVE To retrospectively analyze the clinical symptoms, laboratory findings, and outcomes in patients with microscopic polyangiitis (MPA) who were enrolled in various clinical trials conducted by the French Vasculitis Study Group. METHODS A cohort of 85 patients meeting the Chapel Hill criteria for MPA participated in the study. Seventy-one of them were included in prospective therapeutic trials. Eighty-one diagnoses were biopsy proven. In the other patients, diagnosis was based on clinical findings. RESULTS Forty-seven men and 38 women, with a mean +/- SD age of 56.8 +/- 14.6 years, met the criteria for MPA. Their main clinical symptoms were renal manifestations (78.8%), weight loss (72.9%), skin involvement (62.4%), fever (55.3%), mononeuritis multiplex (57.6%), arthralgias (50.6%), myalgias (48.2%), hypertension (34.1%), lung involvement (24.7%; alveolar hemorrhage 11.8%), and cardiac failure (17.6%). The mean +/- SD serum creatinine level before treatment was 2.59 +/- 2.96 mg/dl; 47 patients had renal insufficiency (serum creatinine > 1.36 mg/dl). Eight patients underwent dialysis at the time of diagnosis, and long-term dialysis was necessary for 10 patients. Antineutrophil cytoplasmic antibodies (ANCA) were present in 38 of 51 patients (74.5%), of whom 33 had a perinuclear staining pattern (pANCA) and 5 had a cytoplasmic pattern. Antibodies to proteinase 3 were present in 4 patients and antibodies to myeloperoxidase were detected in 31, as determined by enzyme-linked immunosorbent assay. Of the 30 patients who underwent renal and celiac angiography, 4 had microaneurysms. Of the 29 patients (34.1%) who had relapses, 8 died during or after the relapse. During followup, 28 of the 85 patients (32.9%) died. The mean +/- SD duration of followup of the group was 69.9 +/- 60.6 months. Deaths were less frequent when patients had been treated with steroids and immunosuppressive drugs (13 patients [24.1%]) than with steroids alone (15 patients [48.4%]) (P < 0.01). The 5-year survival rate was 74%. CONCLUSION This study demonstrated that MPA is a multisystemic disease in which renal symptoms are frequent, but the disease is also associated with general symptoms, arthritis, mononeuritis multiplex, and other manifestations that are also seen in various vasculitides. The rarity of abnormal angiogram findings and the high frequency of pANCA are characteristic of MPA. In most cases, the outcome is comparable with those of other systemic vasculitides, but relapses are frequent.

Bortezomib Plus Dexamethasone Is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial

PURPOSE To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction before stem-cell transplantation in previously untreated myeloma. PATIENTS AND METHODS Four hundred eighty-two patients were randomly assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achieving very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete response (CR/nCR) rate. RESULTS Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%) rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0% v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival (PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and 77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone. CONCLUSION Bortezomib plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.

Long‐term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg‐Strauss syndrome: Analysis of four prospective trials including 278 patients

OBJECTIVE To determine the long-term outcome of patients with polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS), to compare the long-term outcome with the overall French population, to evaluate the impact on outcome of the type of vasculitis, prognostic factors, and treatments administered at diagnosis, and to analyze treatment side effects and sequelae. METHODS Data from PAN, MPA, and CSS patients (n = 278) who were enrolled between 1980 and 1993 were collected in 1996 and 1997 and analyzed. Two prognostic scoring systems, the Five-Factors Score (FFS) and the Birmingham Vasculitis Activity Score (BVAS), were used to evaluate all patients at the time of diagnosis. RESULTS The mean (+/- SD) followup of the entire population was 88.3 +/- 51.9 months (range 3 days to 192 months). Of the 85 deaths recorded, at least 41 were due to progressive vasculitis or its consequences. Death rates reflected disease severity, as assessed by the FFS (P = 0.004) and the BVAS (P < 0.0002), and the 2 scores were correlated (r = 0.69). Relapses, rarer in hepatitis B virus (HBV)-related PAN (7.9%) than in MPA (34.5%) (P = 0.004), occurred in 56 patients (20.1%) and did not reflect disease severity. Survival curves were similar for the subpopulation of 215 patients with CSS, MPA, and non-HBV-related PAN who were given first-line corticosteroids (CS) with or without cyclophosphamide (CYC). However, CS with CYC therapy significantly prolonged survival for patients with FFS scores > or =2 (P = 0.041). Relapse rates were similar regardless of the treatment regimen; only patients treated with CS alone had uncontrolled disease. CYC was associated with a greater frequency of side effects (P < 0.00001). CONCLUSION Rates of mortality due to PAN (related or unrelated to HBV), MPA, and CSS reflected disease severity and were higher than the mortality rate in the general population (P < 0.0004). Rates of relapse, more common in MPA than HBV-related PAN patients, did not reflect disease severity. Survival rates were better among the more severely ill patients who had received first-line CYC. Based on these findings, we recommend that the intensity of the initial treatment be consistent with the severity of the disease. The use of the FFS and BVAS scores improved the ability to evaluate the therapeutic response.

Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

PURPOSE Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. PATIENTS AND METHODS Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. RESULTS After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). CONCLUSION This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

Treatment of adult systemic mastocytosis with interferon‐α: results of a multicentre phase II trial on 20 patients

Summary. Systemic mastocytosis (SM) is characterized by proliferation of mast cells in various organs, which may release a wide variety of mediators, thereby explaining the broad clinical spectrum of disease manifestations. The potentially life‐threatening systemic symptoms and tumoral proliferation are poorly controlled despite the use of several cytotoxic chemotherapies and/or symptomatic treatments. Twenty consecutive adult SM patients with histologically confirmed bone marrow (BM) involvement received interferon‐α subcutaneously (1–5 million units/m2/d, with progressive dose intensification over the first month of treatment) and were evaluated after 6 months of therapy. Seven of them had previously received symptomatic treatments, including steroids, which were ineffective. Among the 13 patients treated for at least 6 months, seven partial and six minor responses, mainly concerning vascular congestion and skin lesions, were obtained, while BM infiltration remained unchanged in 12 patients. The significant reduction of mast‐cell mediator levels after 6 months of treatment was not predictive of clinical remission. The rate of depression was unexpectedly high (seven patients; 35%). Two patients died soon after starting therapy (one myocardial infarction, one septic shock). Six months of interferon‐α may relieve vascular congestion in adults with SM, probably by inhibiting mast‐cell degranulation.

Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma

To the editor: Recent pilot studies combining a cytoreductive autologous stem cell transplantation (ASCT) with a reduced-intensity conditioning regimen (RIC) allograft have reported encouraging results in patients with de novo multiple myeloma (MM).[1][1],[2][2] However, it remains to be determined

Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: A phase 2a study†

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the diseases systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c‐Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality‐of‐life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%−75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long‐term treatment regimens. Am. J. Hematol. 85:921–925, 2010.