French early nationwide idecabtagene vicleucel chimeric antigen receptor T-cell therapy experience in patients with relapsed/refractory multiple myeloma (FENIX): A real-world IFM study from the DESCAR-T registry.

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.

First case of proven invasive pulmonary infection due to Trichoderma longibrachiatum in a neutropenic patient with acute leukemia.

Trichoderma species are saprophytic filamentous fungi that can be found all over the word. These fungi show increasing medical importance as opportunistic human pathogens, particularly in immunocompromised patients. Invasive infections due to Trichoderma are rare and definitive diagnosis is complex to achieve because of the lack of specific diagnosis tools. We report in this work the first proven case of invasive pulmonary infection due to T. longibrachiatum in a 69-year-old white male with hematologic malignancy. The patient was successfully treated initially with voriconazole alone followed by a combination of voriconazole and caspofungine.

[Retrospective study of 25 cases of pulmonary mucormycosis in acute leukaemia]. / Mucormycoses pulmonaires au cours des traitements de leucémies aiguës. Analyse rétrospective d'une série de 25 patients.

INTRODUCTION: In acute leukaemia (AL), the occurrence of pulmonary mucormycosis (PM), the incidence of which is increasing, as a result of chemotherapy induced marrow aplasia, remains a life threatening complication. METHODS: Analysis of clinical, biological and thoracic CT characteristics of patients with PM developing during the treatment of AL between 2000 and 2015. Day 0 (D0) was defined as the day with first CT evidence of PM. RESULTS: Among 1193 patients, 25 cases of PM were recorded during 2099 episodes of bone marrow aplasia. At time of diagnosis of PM, 24/25 patients had been neutropenic for a median of 12 days. None of the patients had diabetes mellitus. On initial CT (D0), the lesion was solitary in 20/25 cases and a reversed halo sign (RHS) was observed in 23/25 cases. From D1 to D7, D8 to D15 and after D15, RHS was seen in 100 %, 75 % and 27 % of cases, respectively. A tissue biopsy was positive in 17/18 cases. The detection of circulating Mucorales DNA in serum was positive in 23/24 patients and in 97/188 serum specimens between D-9 and D9. Bronchoalveolar lavage contributed to diagnosis in only 3/21 cases. The antifungal treatment was mainly based on liposomal amphotericin B combined with, or followed by, posaconazole. A pulmonary surgical resection was performed in 9/25 cases. At 3 months, 76 % of patients were alive and median overall survival was 14 months. CONCLUSION: In AL, early use of CT could improve the prognosis of PM. The presence of a RHS on CT suggests PM and is an indication for prompt antifungal treatment.

Impact of pharmaceutical intervention on quality of life and coping strategies in patients with haematological malignancies.

OBJECTIVES: We conducted a prospective study approved by the local ethics committee to determine the impact of a pharmaceutical intervention (PI) on pain, fatigue, quality of life (QoL) and coping strategies in patients with HMs starting chemotherapy sessions. MATERIAL AND METHODS: Patients received either usual care (UC)+PI (PI group) or UC alone (UC group). They had to complete 2 questionnaires, QLQ-C30 and MAC 21, at 3 different time points: before starting the 1st chemotherapy session (T1), during the intercure (T2) and the day before starting the 2nd chemotherapy session (T3). To determine predictive factors of pain, fatigue, QoL and coping scores at T3, a multivariate ANOVA was used. QoL and coping scores were analysed longitudinally using a linear mixed model. RESULTS: Sixty-eight patients were included in the PI (n=34) or UC groups (n=34). Ninety-two percent of the patients returned all the questionnaires. At inclusion, QoL was significantly better in the PI group (P=0.047). At T3, the group had no influence on pain, fatigue, nor coping scores but a trend towards a better QoL was observed in the PI group (P=0.090). Longitudinally, the PI group did not present significantly better scores on pain, fatigue but both a trend toward better Qol scores and lower anxious preoccupations scores. CONCLUSION: A PI at the beginning of chemotherapy sessions did not have any significant impact on pain and fatigue but a trend towards better Qol scores and lower anxious preoccupations scores.

Emergency and elective pulmonary surgical resection in haematological patients with invasive fungal infections: a report of 50 cases in a single centre.

Invasive fungal infections (IFI) remain life-threatening complications in haematological patients. The aim of the study was to present the experience of a single centre in the surgical treatment of pulmonary IFI. Between 1992 and 2014, 50 haematological patients with IFI underwent pulmonary resection. In 27 cases it was an emergency procedure to avoid haemoptysis (if the lesion threatened pulmonary vessels). The remaining 23 patients underwent elective surgery before new chemotherapy or stem-cell transplantation. Among these patients (median age: 54 years; range: 5-70 years), 92% had acute leukaemia and 68% were on haematological first-line therapy (receiving induction or consolidation chemotherapies). Invasive pulmonary aspergillosis and pulmonary mucormycosis were diagnosed in 37 and 12 patients, respectively. One patient had IFI due to Trichoderma longibrachiatum. All of the patients received antifungal agents. In the month preceding IFI diagnosis, 94% of patients had been neutropenic. At the time of surgery, 30% of patients were still neutropenic and 54% required platelet transfusions. Lobectomy or segmentectomy were performed in 80% and 20% of cases, respectively. Mortality at 30 and 90 days post-surgery was 6% and 10%, respectively. After surgery, median overall survival was 21 months; median overall survival was similar between patients with emergency or elective surgery and between the types of IFI (invasive pulmonary aspergillosis or pulmonary mucormycosis). However, overall survival was far better in haematological first-line patients or in those achieving a haematological complete response than in other patients (p <0.001). In pulmonary IFI, lung resection could be an effective complement to medical treatment in selected haematological patients.

Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma.

BACKGROUND: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. DESIGN: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. RESULTS: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. CONCLUSION: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.

Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion.

After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.

Autologous hematopoietic stem cell transplantation in elderly patients (≥ 70 years) with non-Hodgkin's lymphoma: A French Society of Bone Marrow Transplantation and Cellular Therapy retrospective study.

INTRODUCTION: Limited data is available on the feasibility of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) in elderly patients over 70 years of age with non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: In the setting of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) group, we retrospectively analyzed 81 consecutive patients with NHL over 70 years of age who received AHSCT. RESULTS: The median age at AHSCT was 72.3 years [70-80]. Patients' were diagnosed with diffuse large B-cell lymphoma (n=40), follicular lymphoma (n=16), mantle cell lymphoma (n=15), T-cell lymphoma (n=5), and other (n=5). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was 0 in 73% of patients. Main conditionings were BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=61) and melphalan alone (n=14). Median delays to reach 0.5×109/L neutrophils and 20 × 10(9)/L platelets were of 12 [9-76] days and 12 [0-143] days, respectively. One hundred day and one year cumulative incidence of NRM was 5.4% and 8.5%, respectively. The main cause of death remains relapse. CONCLUSION: In conclusion, this study revealed that AHSCT seemed to be acceptable in patients over 70 years of age with NHL. Patient age is not a limiting factor if clinical condition is adequate.

Generic vancomycin products: Analysis of serum concentrations in patients with acute myeloid leukemia.

UNLABELLED: Concerns have recently emerged about the quality of generic vancomycin products. Our aim is to analyze serum vancomycin concentrations measured 48 hours after the start of an empirical treatment regimen in patients with acute myeloid leukemia (AML) who received one of the two generic vancomycin products available in France. PATIENTS AND METHODS: Seventy-nine AML patients treated with vancomycin during two study periods were included in the study. Our vancomycin dosing regimen was based on the patients' total body weight adjusted for renal clearance. RESULTS: A total of 93 serum vancomycin concentrations were collected: 31 in period 1 and 62 in period 2. In bivariate analysis, the mean serum vancomycin concentrations were not significantly different (19.9 ± 11.2 mg/L in period 1 vs 18.9 ± 6.0 mg/L in period 2, P=0.64). In the final generalized estimating equations model, serum vancomycin concentrations correlated statistically with a positive coefficient for age (P<0.001) and with negative coefficients for male sex (P=0.001) and hemoglobin level (P=0.021). CONCLUSION: Serum vancomycin concentrations measured 48 hours after the start of an empirical treatment were not influenced by the nature of the generic product but correlated with age, sex and hemoglobin level in AML patients.

Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients.

Deletions of the 1p region appear as a pejorative prognostic factor in multiple myeloma patients (especially 1p22 and 1p32 deletions) but there is a lack of data on the real impact of 1p abnormalities on an important and homogeneous group of patients. To address this issue we studied by fluorescence in situ hybridization (FISH) the incidence and prognostic impact of 1p22 and 1p32 deletions in 1195 patients from the IFM (Institut Francophone du Myélome) cell collection. Chromosome 1p deletions were present in 23.3% of the patients (271): 15.1% (176) for 1p22 and 7.3% (85) for 1p32 regions. In univariate analyses, 1p22 and 1p32 appeared as negative prognostic factors for progression-free survival (PFS): 1p22: 19.8 months vs 33.6 months (P<0.001) and 1p32: 14.4 months vs 33.6 months (P<0.001); and overall survival (OS): 1p22: 44.2 months vs 96.8 months (P=0.002) and 1p32: 26.7 months vs 96.8 months (P<0.001). In multivariate analyses, 1p22 and 1p32 deletions still appear as independent negative prognostic factors for PFS and OS. In conclusion, our data show that 1p22 and 1p32 deletions are major negative prognostic factors for PFS and OS for patients with MM. We thus suggest that 1p32 deletion should be tested for all patients at diagnosis.

The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?

BACKGROUND: Pulmonary mucormycosis (PM) is a life-threatening fungal infection with an increasing incidence among patients with acute leukemia. In some immunocompromised hosts, the reversed halo sign (RHS) has been described on the pulmonary computed tomographic (CT) scan of patients with mucormycosis. METHODS: This study reports a single-center experience with PM exclusively in patients with acute leukemia. Clinical records, laboratory results, and CT scans were retrospectively analyzed to evaluate the clinical usefulness of the RHS for the early identification and treatment of PM, with regard to outcomes in these patients. RESULTS: Between 2003 and 2012, 16 cases of proven PM were diagnosed among 752 consecutive patients receiving chemotherapy for acute myeloblastic or lymphoblastic leukemia. At the time PM was diagnosed, all patients but one were neutropenic. The study of sequential thoracic CT scans showed that during the first week of the disease, the RHS was observed in 15 of 16 patients (94%). Initially, other radiologic findings (multiple nodules and pleural effusion) were less frequent, but appeared later in the course of the disease (6% and 12% before vs 64% and 55% after the first week). After the diagnosis of PM, median overall survival was 25 weeks (range, 3-193 weeks), and 6 patients (38%) died before day 90. CONCLUSIONS: In the particular setting of neutropenic leukemia patients with pulmonary infection, the presence of the RHS on CT was a strong indicator of PM. It could allow the early initiation of appropriate therapy and thus improve the outcome.

[Place of surgery in pulmonary aspergillosis and other pulmonary mycotic infections]. / Place de la chirurgie dans les maladies aspergillaires et autres mycoses pulmonaires.

Surgery is part of the therapeutic strategy of aspergillosis and mucormycosis. The aspergilloma is defined as a rounded mass, developing in a cavity by the proliferation of spores of Aspergillus. The most common complication was haemoptysis reported in 50-95% of cases. The pleuropulmonary lesions predisposing are: tuberculosis, residual pleural space, emphysema and lung destroyed by fibrosis or radiotherapy or bronchiectasis. The indications for surgery depend on symptoms, respiratory function, the parenchyma and the type of aspergilloma (simple or complex). In a patient with an intrapulmonary aspergilloma, lung resection preceded by embolization is recommended based on respiratory function. For intrapleural aspergilloma, thoracoplasty is recommended according to the patient's general condition. The invasive pulmonary aspergillosis (IPA) is characterized by an invasion of lung tissue and blood vessels by hyphae in immunocompromised patients. The death rate of patients who have an API after treatment for leukemia or lymphoma was 30 to 40%, after bone marrow transplantation 60%, after solid organ transplantation from 50 to 60% and after any other cause of immunocompromising from 70 to 85%. The main cause of these deaths is massive hemoptysis. Surgery (lobectomy) is indicated for the prevention of hemoptysis when the mass is in contact with the pulmonary artery or one of its branches, and if it increases in size with the disappearance of border security between the mass and the vessel wall. The patient will be operated in an emergency before the white blood cells do not exceed the threshold of 1000 cells/µl. A persistent residual mass after antifungal treatment may justify a lung resection (lobectomy or wedge) before a new aggressive therapy. Mucormycosis affects patients following immunocompromising states--haematologic malignancy, diabetes mellitus, transplantation, burns and malnutrition. The treatment of pulmonary mucormycosis combines surgical and medical approach.

Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program.

One hundred and ten patients with multiple myeloma were treated with bendamustine as part of a French compassionate use program. To receive bendamustine, patients had to present with relapsed or refractory disease after prior therapies that had to include alkylators, steroids, IMiDs and bortezomib. The median number of bendamustine cycles administered was 4 (1-13). The overall response rate (≥ partial response) was 30%, including 2% complete responses. The median progression-free and overall survival for the entire cohort were 9.3 and 12.4 months, respectively. In this series of patients with advanced disease, both the response rate and the duration of response are encouraging and indicate that bendamustine presents a feasible option, which should be considered for the treatment of relapsed/refractory patients.

Ancestim (r-metHuSCF) plus filgrastim and/or chemotherapy for mobilization of blood progenitors in 513 poorly mobilizing cancer patients: the French compassionate experience.

Ancestim (r-MetHuSCF) is available in France for compassionate use in patients who are candidates for high-dose chemotherapy and autologous transplantation, and who failed in previous attempts at mobilization and collection. We report here data from 513 adult patients who benefited from this program, between January 1998 and July 2007. Given with systematic premedication, ancestim was generally well tolerated, although severe but not life-threatening adverse events were reported in 12 individuals. Overall, a graft was obtained or completed for 235 patients (46%). The median number of collected CD34+ cells was 3.00 × 10(6)/kg (range: 0.03-39.50). The target threshold of 2 × 10(6) CD34+ cells/kg was reached in 161 patients (31%). Factors associated with collection were diagnosis of myeloma, no previous autologous transplant, no more than one previous failed attempt and a mobilization regimen including cytotoxic agents. A total of 207 patients (40%) proceeded to high-dose chemotherapy and autologous transplantation. The median time to reach 0.5 × 10(9)/L neutrophils and 20 × 10(9)/L platelets was 12 (6-40) and 13 (0-31) days, respectively. We conclude that a combination of ancestim with filgrastim successfully mobilized CD34+ cells in peripheral blood, and allowed adequate collection in preparation for autologous transplantation in approximately one-third of poorly mobilizing patients.

Cost effectiveness of posaconazole in the prophylaxis of invasive fungal infections in acute leukaemia patients for the French healthcare system.

BACKGROUND: Acute myeloblastic leukaemia (AML) patients are at high risk of suffering from invasive fungal infections (IFI). Posaconazole demonstrated higher efficacy than standard azole agents (SAA) in the prophylaxis of IFI in this population. The authors estimated the cost effectiveness of posaconazole versus SAA in France. METHODS: A decision-tree model was developed to compare posaconazole with SAA with the results of a published clinical trial. Clinical events were modelled with chance nodes reflecting probabilities of IFI, IFI-related death, and death from other causes. Medical resource consumption and costs were obtained from results of the clinical trial and from a dedicated survey on the costs of treating IFI using a retrospective chart review design. RESULTS: IFI treatment costs were estimated using medical files from 50 AML patients from six French centres, with a proven and probable IFI, who had been followed-up for 298 days on average. Direct costs directly related to IFI were estimated at €51,033, including extra costs of index hospitalisation, costs of antifungal therapy and additional hospitalisations related to IFI treatment. The model indicated that the healthcare costs for the posaconazole strategy were €5,223 (€2,697 for prophylaxis and €2,526 for IFI management), which was €859 less than the €6,083 in costs with SAA (€469 for prophylaxis and €5614 for IFI management). A sensitivity analysis indicated that there was an 80% probability that prophylaxis using the posaconazole strategy would be superior. CONCLUSION: The findings from this analysis suggest that posaconazole use is a clinically and economically dominant strategy in the prophylaxis of IFI in AML patients, given the usual limits of economic models and the uncertainty of costs estimates.

A retrospective series of gut aspergillosis in haematology patients.

Gut invasive aspergillosis is an extremely rare infection in immunocompromised patients. The goal of this retrospective multicentre study is to report on cases of gut aspergillosis in haematology patients, including clinical presentation, risk factors, and outcome. Twenty-one patients from nine centres were identified. Eight had isolated gut aspergillosis, with no evidence of other infected sites, and 13 had disseminated aspergillosis. Thirteen patients had acute leukaemia. Nine were allogeneic stem cell transplant recipients. Clinical symptoms and imaging were poorly specific. The galactomannan antigenaemia test result was positive in 16/25 (64%) patients, including in four of the eight cases of isolated gut aspergillosis. Five of 21 patients had a dietary regimen rich in spices, suggesting that, in these cases, food could have been the source of gut colonization, and then of a primary gut Aspergillus lesion. The diagnosis was made post-mortem in six patients. The mortality rate in the remaining patients at 12 weeks was 7/15 (47%). Gut aspergillosis is probably misdiagnosed and underestimated in haematology patients, owing to the poor specificity of symptoms and imaging. Patients with a persistently positive galactomannan antigenaemia finding that is unexplained by respiratory lesions should be suspected of having gut aspergillosis in the presence of abdominal symptoms, and be quickly investigated. In the absence of severe abdominal complications leading to surgery and resection of the lesions, the optimal treatment is not yet defined.

Prospective survey of indoor fungal contamination in hospital during a period of building construction.

An 18-month survey of indoor fungal contamination was conducted in one haematology unit during a period of construction work. Air was sampled with a portable Air System Impactor and surfaces with contact Sabouraud plates. During this survey the mean concentration of viable fungi in air was 4.2 cfu/m(3) and that for surfaces was 1.7 cfu/plate. At the beginning of construction work, there were increases in airborne fungal spores (from 3.0 to 9.8 cfu/m(3)) in the unit, but concentrations did not exceed 10 cfu/m(3) during the 18-month period. The most frequently recovered airborne fungi were Penicillium spp. (27-38%), Aspergillus spp. (25%) and Bjerkandera adusta, a basidiomycete identified with molecular tools (7-12%). Blastomycetes accounted for more than 50% of the fungal flora on surfaces. Investigating the impact of a new air-treatment system (mobile Plasmair units), there were significant reductions in fungal contamination for the Plasmer -treated rooms, and in these rooms we observed the same level of fungal load whether construction work was in progress or not.