Denis Caillot

Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis

To evaluate the efficacy and safety of voriconazole in acute invasive aspergillosis (IA), an open, noncomparative multicenter study was conducted. Immunocompromised patients with IA were treated with intravenously administered voriconazole 6 mg/kg twice a day (b.i.d.) twice and then 3 mg/kg b.i.d. for 6-27 days, followed by 200 mg b.i.d. administered orally for up to 24 weeks. Response was assessed by clinical and radiographic change. A total of 116 patients were assessable. IA was proven in 48 (41%) and probable in 68 patients. Voriconazole was given as primary therapy in 60 (52%). Good responses were seen in 56 (48%); 16 (14%) showed complete response and 40 (34%) partial response. A stable response was seen in 24 patients (21%), and 36 (31%) of the infections failed to respond to therapy. Good responses were seen in 60% of those with pulmonary or tracheobronchial IA (n=84), 16% with cerebral IA (n=19), 58% with hematologic disorders (n=67), and 26% of allogeneic stem cell transplant recipients (n=23). Voriconazole is efficacious in treating acute IA.

Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.

BACKGROUND High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation. METHODS We randomly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse. The primary end point was progression-free survival. RESULTS Lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β(2)-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=0.002). Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide (40 months, vs. 23 months with placebo; P<0.001). CONCLUSIONS Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).

Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery.

PURPOSE The prognosis of invasive pulmonary aspergillosis (IPA) occurring in neutropenic patients remains poor. We studied whether new strategies for early diagnosis could improve outcome in these patients. PATIENTS AND METHODS Twenty-three histologically proven and 14 highly probable IPAs in 37 hematologic patients (neutropenic in 36) were analyzed retrospectively. RESULTS The most frequent clinical signs associated with IPA were cough (92%), chest pain (76%), and hemoptysis (54%). Bronchoalveolar lavage (BAL) was positive in 22 of 32 cases. Aspergillus antigen test was positive in 83% of cases when tested on BAL fluid. Since October 1991, early thoracic computed tomographic (CT) scans were systematically performed in febrile neutropenic patients with pulmonary x-ray infiltrates. This approach allowed us to recognize suggestive CT halo signs in 92% of patients, compared with 13% before this date, and the mean time to IPA diagnosis was reduced dramatically from 7 to 1.9 days. Among 36 assessable patients, 10 failed to respond (amphotericin B [AmB] plus fluorocytosyne, n = 2; itraconazole + AmB, n = 8) and died of aspergillosis. Twenty-six patients were cured or improved by antifungal treatment (itraconazole with or without AmB, n = 22; voriconazole, n = 4). In 15 of 16 cases, surgical resection was combined successfully with medical treatment. Achievement of hematologic response, early diagnosis, unilateral pulmonary involvement, and highest level of fibrinogen value < 9 g/L were associated with better outcome. CONCLUSION In febrile neutropenic patients, systematic CT scan allows earlier diagnosis of IPA. Early antifungal treatment, combined with surgical resection if necessary, improves IPA prognosis dramatically in these patients.

Increasing Volume and Changing Characteristics of Invasive Pulmonary Aspergillosis on Sequential Thoracic Computed Tomography Scans in Patients With Neutropenia

PURPOSE In patients with neutropenia, thoracic computed tomography (CT) halo and air-crescent signs are recognized as major indicators of invasive pulmonary aspergillosis (IPA). Nevertheless, the exact timing of CT images is not well known. PATIENTS AND METHODS Seventy-one thoracic CT scans were analyzed in 25 patients with neutropenia with surgically proven IPA. RESULTS On the first day of IPA diagnosis with early CT scan (d0), a typical CT halo sign was observed in 24 of 25 patients. At that time, the median number of thoracic lesions was two (range, one to six), and pulmonary involvement was bilateral in 12 cases. The halo sign was present in 68%, 22%, and 19% of cases on d3, d7, and d14, respectively. Similarly, the air-crescent sign was seen in 8%, 28%, and 63% of cases on the same days. Otherwise, a nonspecific air-space consolidation aspect was seen in 31%, 50%, and 18% of cases on the same days. The analysis of calculated aspergillary volumes on CT showed that, despite antifungal treatment, the median volume of lesions increased four-fold from d0 to d7, whereas it remained stable from d7 to d14. Overall, 21 patients (84%) were cured by the medical-surgical approach. CONCLUSION In patients with neutropenia, CT halo sign is a highly effective modality for IPA diagnosis. The duration of the halo sign is short, and it demonstrates the value of early CT. The increase of the aspergillosis size on CT in the first days after IPA diagnosis is not correlated with a pejorative immediate outcome when using a combined medical-surgical approach.

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.

Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)

PURPOSE Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters. PATIENTS AND METHODS A series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p). RESULTS We found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients. CONCLUSION Short-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction.

Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma.

The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction before high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally randomly assigned to receive VD or vtD. After 4 cycles, the complete response (CR) rate was the same in both groups (13% in the vtD arm, 12% in the VD arm, P = .74). However, the CR plus very good partial response (VGPR) rate was significantly higher in the vtD arm (49% vs 36%, P = .05). After ASCT, the CR plus VGPR rate was significantly higher in the vtD arm (74% vs 58%, P = .02). The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy (PN): grade ≥ 2 PN were reported in 34% in the VD arm versus 14% in the vtD arm (P = .001). vtD, including reduced doses of bortezomib and thalidomide, yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT.

Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients

We retrospectively investigated the feasibility and the toxicity of autologous stem cell transpantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high‐dose melphalan (HDM) alone (n = 18) or in combination with 12 Gy total body irradiation (n = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow‐up of 14 months, the OS and the EFS rates at 4 years were 57.1% (±10.8) and 29.9% (±14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance <30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4‐year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra‐haematological toxicity, ASCT should not be considered in other cases.

Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide–refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02

The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).

Liposomal Amphotericin B in Combination With Caspofungin for Invasive Aspergillosis in Patients With Hematologic Malignancies : A Randomized Pilot Study (Combistrat Trial)

Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds.