French Innovation Research Articles

Long-term results of Waldenström macroglobulinaemia treatment by bendamustine and rituximab: A study on behalf of the French Innovative Leukemia Organization (FILO).

The bendamustine-rituximab (BR) schedule is an efficient first-line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months (95% confidence interval [CI] 69.9-80.6), 5-year outcome is still excellent at 66.63% (95% CI 56.09-79.17) for PFS and 80.01% (95% CI 70.82-90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99-27.64) at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this schedule. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.

Acute Myeloid Leukemia Patients Who Stopped Venetoclax or/and Azacytidine for Other Reasons Than Progression Have a Prolonged Treatment Free Remission and Overall Survival. a Filo Study

Background Recent update of the VIALE-A study showed a long-term survival for approximately 30% of acute myeloid leukemia (AML) patients treated with venetoclax and azacitidine (VEN-AZA) for a newly-diagnosed AML (ND-AML) (Pratz K.W et al., ASH 2022). A recent report of a small cohort of responding patients who interrupted VEN-AZA displayed a sustained treatment-free remission (TFR) period suggesting that treatment interruptions might be considered (Chua CC. et al., Blood Adv. 2022). To evaluate the impact of VEN-AZA discontinuation on survival and time without treatment, we retrospectively analyzed the characteristics and outcomes of patients who stopped VEN and/or AZA for reasons other than progression (e.g. hematological or other toxicities). We presented the first 51 patients from our cohort last year at ASH meeting (Garciaz S. et al, ASH 2022). In this abstract, we analyzed separately ND-AML and relapsed/refractory (R/R) AML. Methods Eligible patients 1) have been treated with VEN-AZA for a ND or R/R AML, 2) have stopped AZA and/or VEN for more than 3 months, 3) are in remission (CR, CRi or Morphologic leukemia-free state, [MLFS]) at the time of treatment interruption, 4) are ≥ 18-year-old. Main endpoints were overall survival (OS) and treatment-free remission (TFR) calculated from the time between the last day of VEN to relapse, retreatment, or death. We measured the impact of prognostic factors on OS by a Cox regression taking disease status (ND vs R/R), the discontinued treatment (VEN vs VEN-AZA), the cytogenetics and NPM1 or IDH mutations. Results We included 83 patients from French Innovative Leukemia Organization (FILO) centers and Moffit Cancer Center (US) treated with VEN-AZA for a ND-AML or a R/R AML between 11/18 and 07/23. Regarding the ND-AML patients (n=60; 32 males and 28 females), the median age was 76 (range, 26-86.5), median platelet count, WBC, ANC and bone marrow blast involvement was 52 G/L (range, 9-296), 2.8 G/L (range, 0.6-200), 0.6 G/L (range, 0.02-31.6) and 40% (range, 10-99), respectively. Cytogenetics was intermediate (int.) in 48 cases (80%) and unfavorable (unfav.) in 12 patients (20%). Eleven AML (18.3%) had NPM1 mutations, and 19 (31.6%), IDH alterations including 7 IDH1, 8 IDH2R140 and 4 IDH2R172. Six (10%) and 5 (8.3%) patients had FLT3 or TP53 mutations, respectively. The median number of VEN-AZA cycle was 4 (1-17). The best response was CR (n=44, 73.3%), CRi (n=13, 18.3%) and MLFS (n=3, 5%). Twenty-one patients out of 25 (78%) reached MRD negativity assessed by molecular (n=11) or flow cytometry (n=10) techniques. Twenty-six patients (43.3%) stopped VEN-AZA and 34 (56.7%) stopped VEN and continued AZA monotherapy for a median number of 7 AZA cycles (1-41). Reasons for treatment discontinuation were prolonged cytopenia, non-hematological toxicities, patient choice or unknown in 35 (58%), 6 (10%), 8 (13.3%), and 11 (18.3%) patients, respectively. We registered 27 relapses and 24 deaths. Fourteen patients were retreated including 11 patients who were rechallenged with VEN-AZA. Second CR/CRi rate with VEN-AZA was 3/11 (27.7%). With a median follow of 23 months, median TFR was 15 months (ranges, 3-47) and median OS was 44 months (ranges, 7-50). We also analyzed a smaller cohort of 23 R/R responding patients who stopped AZA and/or VEN. The median age was 73, median number of previous lines was 1 (1-3). Twenty-one patients (91.3%) received prior intensive chemotherapy and 4 (17.4%) prior allogeneic hematopoietic transplantation. Cytogenetic risk was int. in 17 (73.9%) and unfav. in 5 patients (21.7%) and missing in one patient. NPM1 and IDH genes were mutated in 6 (26%) and 10 (43.4%) cases, respectively. Sixteen patients (69.6%) stopped VEN-AZA and 7 (30.4%) interrupted VEN only. Nine patients resumed a treatment including 6 patients rechallenged with VEN-AZA. Among them, 3/6 (50%) obtained a second CR/CRi. Median TFR and OS were 10 (ranges, 3-23) and 19 (ranges, 7-32), respectively. Factor impacting OS in multivariate analysis were R/R AML disease status (Hazard Ratio [HR] =0.47, ranges, 0.23-0.87), and IDH mutations (HR= 2.1, ranges, 1.05-4.34), but not unfav. cytogenetics, NPM1 mutations, or the discontinued treatment (VEN vs VEN-AZA). Conclusion: Discontinuation of VEN and/or AZA in responding patients was associated with sustained responses and long-term survival rates. Resuming treatment may induce a second remission in some patients.

Lenalidomide Consolidation Improves Measurable Residual Disease (MRD) Rates and Progression Free Survival in Patients with Chronic Lymphocytic Leukemia Following Initial FCR Chemotherapy - Final Analysis of CLL6 Residuum Study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO)

Introduction Eradication of MRD after first line chemoimmunotherapy (CIT) correlates with longer progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients. Lenalidomide (LEN) has antiproliferative and immunomodulatory effects in CLL and may improve response following CIT (Buhler et al 2016; Fink et al 2017). Here we report the final analysis of the phase III, randomized, CLL6 RESIDUUM trial, that aimed to determine whether LEN improves immunophenotypic (IP) complete response (CR) rates and extends remission duration in patients with CLL who have MRD following induction CIT. Methods The CLL6 trial was a joint trial of the ALLG and the FILO. CLL patients with CIRS score <6 requiring treatment according to iwCLL received 4 to 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). After completion of treatment, patients with clinical, radiological and/or flow cytometry evidence of MRD in blood (PB) or bone marrow (BM) were randomized 1:1 to receive 2 years of 10 mg daily LEN consolidation or observation (OBS). High sensitivity (HS) MRD were scheduled at month 3, 6 and every 6 months until month 24 then every 12 months until month 72 in PB and at screening and on months 12 and 24 in BM. The primary endpoint was time to clinical disease progression, or death, from randomization. The study planned to randomize 192 patients to detect a hazard ratio of 1.94, i.e., an increase in the % of patients remaining progression free at 4 years to 70% in the LEN arm compared with 50% in the OBS arm (two-sided log rank test at alpha = 0.05, no competing risks or loss to follow up, power = 0.86). Results The study closed prematurely because of an acute lymphoblastic leukemia (ALL) warning (3 of 56 patients [5.4%]) in the CLLM1 trial (Fink et al., 2017; Fürstenau et al., 2021). Between May 2011 and January 2018, 143 patients were randomized (70 in Australia and 73 in France) to the LEN (n=71) or OBS (n=72) arms. Median age was 63 [range 41-78], and 60 [26-79] years in the LEN and OBS arms respectively, 113 patients were males. At randomization, 27 (38 %) and 23 (32%) patients were in CR, 9 (13%) and 10 (14%) in nPR, 35 (49%) and 39 (54%) in PR in LEN and OBS arms respectively. Forty-nine (69%) and 47 (65%) had PB and 56 (79%) and 58 (81%) had BM detectable MRD in LEN and OBS arm respectively. Median follow-up (FU) is 52.6 months (range 44.9-59.0; LEN 49.8 [41.9-57.1], OBS 55.59 [44.0-61.7]). Twenty-eight (39%) patients progressed in the LEN arm versus 40 (56%) in the OBS arm (χ² p=0.01), 8 died in each arm. Median PFS was 64.6 (95%CI 47.7-not reached [NR]) months in the LEN arm versus 42.4 (32.3-61.6) months in the OBS arm (p=0.039). Multivariate analysis did not identify any predictive factor of relapse. Median overall survival was not reached (NR) (77.58-NR) in the LEN arm and 107.7 (107.6-NR) months in the OBS arm. There were 118 adverse events (AE), 87 in the LEN and 31 in the OBS arms respectively, with more neutropenia (n=21 vs n=1), gastrointestinal (n=10 vs n=4), respiratory (n=9 vs n=0) nervous system (n=6 vs n=1) and musculoskeletal (n=4 vs n=1) in the LEN arm. Most of the excess of AEs in LEN arm occurred after the end of the treatment. Severe AEs were reported in 35 patients (24.5%), 24 in the LEN arm and 11 in OBS. Fifteen secondary malignancies occurred: 8 in the LEN arm; 7 in the OBS arm. Six were of hematological origin (2 Richter transformation in each arm, 1 marginal zone lymphoma in the OBS arm and 1 myelodysplastic syndrome in the LEN arm). No case of ALL occurred. HS MRD analyses were performed in 71/73 patients in the French cohort. A follow-up was available in 65/71 with a median number of 7 time-points per patients (range 3-10). Different MRD kinetics were observed. While MRD rates in OBS arm increased in 33/34 patients, LEN consolidation led to long-lasting and transient deep IP CR in 4/31 and 9/31 patients respectively, MRD rate stabilization in 10/31 patients, and MRD increase in the remaining 6/31 patients. Conclusion The CLL6 RESIDUUM study demonstrated a significant benefit of consolidation therapy with lenalidomide in CLL patients with residual disease after FCR treatment. LEN resulted in a significantly longer PFS, with no unacceptable toxicity including ALL. Although FCR is no longer considered gold standard initial CLL therapy, eradicating residual disease can remain challenging with newer targeted agents. Patients with CLL MRD following initial therapy may experience prolongation in progression free survival from LEN consolidation.

Innovation Culture in French Organisations

The aim of this study was to measure the relative impact of culture and processes on innovation performance. Contrary to processes, culture represents all implicit factors influencing daily behaviour. Culture gathers the unwritten rules of the social game and serves as social cement for an organisation. Processes correspond to identified and formalised practices and rules, including having a dedicated team or qualified collaborators for running product design and development, for example. Based on the scientific literature, we designed a survey to assess these three sides of innovation (culture, processes and performance). We analysed the answers of 432 French innovation managers in order to identify the predictors of Innovation performance. The whole model appears highly explanatory and shows that innovation culture holds a predictive power nearly four times as high as innovation processes. In particular, eagerness for radical change, which is not so common in French organizations, is the strongest predictor of innovation performance. Collective discovery skills and innovation climate were also good predictors of innovation performance, whereas risk aversion and tradition appear as marginal negative predictors. . These results are original because practitioners and researchers mainly produce guidelines focused on innovation processes, methods and tools as if they were the only drivers of innovation. However, the major challenge for stimulating innovation could be to understand the organization’s culture and design processes that will be both congruent to the existing culture and likely to initiate a first step to cultural change, which remains long and uncertain.

British-French Technology Transfer from the Revolution to Louis Philippe (1791–1844): Evidence from Patent Data

This paper examines the patterns of technology transfer from Britain to France during the early phases of industrializing using a dataset comprising all patents granted in France in the period 1791–1844. Exploiting the peculiarities of French legislation, we construct an array of patent quality indicators and investigate their determinants. We find that patents filed by British inventors or French inventors with personal connections to British inventors were of relatively higher quality. Overall, our results show that the French innovation system was capable of attracting and effectively absorbing key technologies from Britain.

DEATH Historiography In Islam dan French historical tradition: Study on Wafiyāt al-A’yān wa Abnāu Abnāi Zamān and Western Attitude Toward death from The Middle Age to The Present

Historiography of death between Arab-Islam and French tradition has different root and models. As Arabian model wafiyat came into being as new systematic mode of writing bibliographical dictionary, it is French la histoire la morte was the French innovation in social history by Annales school. To make clear comparison, two book are selected that are Wafiyāt al-A’yān wa Abnāu Abnāi Zamān by Ibn Khalikan and Attitude tward Death by Philip Aries. To study these two books, comparative historiography is applied to make a comparison and contrast between genre, style and sources. As the result of taking study of comparison, so there are similarity and differences between two historical tradition in the from of content and method of writing history. These two types are similar in one common trait constructed the idea based on death. However, it is clearly different in as much as that Arabic wafiyat is prosopography and has relgious content and intend; meanwhile French death historiography is social history and growth in the idea of study of mentalites.

An Evaluation of the French Innovation Tax Credit

An Evaluation of the French Innovation Tax Credit

Long-Term Follow-up of Bendamustine Plus Rituximab Regimen in 69 Treatment Naïve (TN) Patients with Waldenström Macroglobulinemia, a Study on Behalf of the French Innovative Leukemia Organization (FILO)

Background Waldenström macroglobulinemia (WM) is a rare hematological malignancy characterized by the accumulation of IgM-secreting clonal lymphoma cells with a lymphoplasmacytic morphological differentiation. Recently, BTK inhibition has emerged as a promising therapeutic strategy in WM (Buske, JCO 2022; Tam, Blood 2020). However, in real life, a large part of patients(pts) continue to be treated by chemoimmunotherapy (Buske, Lancet Hematol2018) including bendamustine (B)-rituximab (R) in salvage (Tedeschi , Leukemia Lymphoma 2015) or first line MW (Treon, ASH2016). We have previously reported a series of 69 WM pts treated by BR (Laribi, BJH 2018) and demonstrated that this regimen is efficient. However, the follow-up was relatively short and some questions remained unresolved in terms of long-range response and second cancer occurrence. Here we report results of this series with a longer follow-up. Methods Sixty-nine symptomatic previously untreated pts with WM diagnostic criteria according to the second WM Workshop recommendations were enrolled in this retrospective multi-center study between January 2013 and December 2017 in 13 French centers. MYD88L265P and CXCR4 mutations were searched using qPCR and or next generation sequencing. Del(17p) and/or TP53 mutation were investigated in 34 pts. All pts received a BR regimen consisting of 375 mg/m2 of R on day 1 and 90 mg/m2 of B on days 1 and 2, repeated every 4 weeks, with a maximum of 6 cycles. Cumulative incidence of secondary malignancies and high-grade lymphomas were computed, considering death free of malignancies as a competing event. Event-free survival (EFS), time to next treatment (TNT), progression-free survival (PFS) and overall survival (OS) were plotted using the log rank test and Kaplan-Meier graphical comparison. Results Pts median age was 69 years old (yo; range 45-88) at WM diagnosis and 71 yo (range 46-88) at therapy initiation. MYD88 and CXCR4 mutations were present in 45/51 (88%) and 11/44 (25%) of pts, respectively. A complex karyotype was disclosed in 6/44 (14%) pts, and 1/34 (3%) had TP53 alteration. According to the IPSSMW score, 14 (22%) pts were low risk, 32(46%) intermediate, and 32 (46%) high risk. Using consensus response criteria, the overall response rate was 97% (very good partial response [VGPR] with negative immunofixation 19%, VGPR 37%, PR40%, MR 1%) and the major response rate was 96%. Cumulative incidence of VGPR or better was 47.8%, 53.6%, 55%, and 56% at 6, 12, 18, and 24 months, respectively. After a median observation time of 68.5 months (range 23.13-106) post BR, the median OS was not reached (83-NR) , and the median PFS was 82 months (75-NR). Median OS for pts with mutated or WT MYD88 was NR and 72.8 months, respectively (p=0.046). Median OS for pts with mutated or WT CXCR4 was 70.2 months and NR, respectively (p=0.64). Median OS related to disease or treatment was not reached, while median OS related to other causes was 106 months. Sixteen (23.2%) pts relapsed. Fourteen received second line therapy and 2 supportive care. Eight patients received ibrutinib, and 6 chemo-immunotherapy. TNT was 31.55 months (range 2.66-82.43). Median PFS after a second line of treatment (PFS2) was 45 (9.13-NR) or 21 months (range 9.13-NR), for pts receiving ibrutinib or not. Eleven pts developed a second cancer: 9 solid tumors (2 pancreatic, 2 gastric, 1colic, 1 pulmonary, 1 breast, 1 cutaneous), and 2 treatment-related myeloid neoplasms (TRMN). Median EFS, defined as occurrence of death, relapse or second cancer was 82 months (61-NR). The cumulative incidence of second cancer was 2.90%, 5.80%, 10.49%, and 17.6% at 12, 24, 48, and 96 months, respectively (figure 1). Univariate analyses on OS disclosed statistically significant differences for age at diagnosis (p=0.001), age at first therapy (p <0.001), IgM>70g/L (p: 0.018), complex karyotype (p=0.037), and high risk IPSSMW (p<0.01). In multivariate analysis, only IPSSMW remained statistically significant (p<0.001) (table1). Univariate analyses on PFS only singled out age at diagnosis (p=0.03) or at first therapy (p=0.049) as statistically significant. Mutated MYD88 or CXCR4 did not impact OS nor PFS. Conclusion This study demonstrates that the BR regimen is efficient in treatment naïve WM pts, yielding long-term responses. The occurrence of secondary cancers, including TRMN, should be closely monitored in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Survival of Acute Myeloid Leukemia Responding Patients Who Stopped Azacytidine and/or Venetoclax Because of Poor Tolerance or Physician Choice: A Retrospective Multicenter Study from the French Innovative Leukemia Organization (FILO)

Background: Acute myeloid leukemia (AML) patients treated upfront with venetoclax and azacitidine (VEN-AZA) achieved a 66.4% composite complete response (CRc) including 36.7% complete response (CR) and 29.7% CR with incomplete hematologic recovery (CRi) in the VIALE-A trial (DiNardo et al., 2020). Median event-free survival (EFS) and duration of response were 9.8 months (95% CI, 8.4 to 11.8) and 17.8 months, respectively. These good results are mitigated by an 82% rate of hematologic adverse events and a 42 to 54% risk of febrile neutropenia both in clinical trial and real-life studies. A recent report of a small cohort of 13 patients in CRc for ≥12 months who interrupted VEN-AZA showed that these patients maintained long treatment-free remission period (Chua et al., 2022) suggesting that treatment interruptions might be considered. To evaluate the impact and the safety of this strategy, we designed a retrospective multicentric study of responding patients who stopped VEN and/or AZA. Methods: Eligible patients had to 1) have been treated with VEN-AZA for previously untreated or pretreated AML, 2) have stopped VEN or AZA for more than 3 months because of poor tolerance and/or physician choice, 3) be in response (CR, CRi or Morphologic leukemia-free state, [MLFS]) at the time of treatment interruption, 4) be aged ≥18 years. Main endpoints were overall survival (OS), event-free survival (EFS), and treatment-free remission (TFR). We measured the impact of prognostic factors on long-term survival by calculating hazard ratios (HR) in univariate and multivariate analyses. Results: We included 51 patients from 12 centers of the FILO group treated with VEN-AZA upfront (n=35, 68.6%) or as salvage treatment (n=16, 31.4%), between 01/19 and 02/22. Next Generation Sequencing (NGS) and minimal residual disease (MRD) data were available for 38 (74.5%) and 28 (55%) patients, respectively. Median age was 75 (ranges, 22-89). WHO classification AML was de novo, AML with myelodysplastic-related changes and therapy-related AML for 27 (52.9%), 21 (41.2%) and 3 (5.9%) patients, respectively. Median platelet count, total white blood cell count and median absolute neutrophile count were 52 G/L (ranges, 7-259), 1.9 (ranges, 0.5-95.5) and 0.7 (ranges, 0-31.6), respectively. Median bone marrow blasts involvement was 32% (range, 7-99). Fourteen patients (27.5%) had adverse cytogenetics. NPM1 and FLT3 mutations were found in 9 (17.6%) and 4 (7.8%) patients, respectively. Twenty (39.2%) patients had a IDH mutation (IDH1, n=5 [9.8%]; IDH2R140 n=9 [17.6%] and IDH2R172, n=6 [11.8%]). TP53 mutation was mutated in 5 (9.8%) cases. Patients received a median of 4 cycles of VEN-AZA (ranges, 1-15); response were CR, CRi and MLFS for 33 (64.7%), 14 (27.5%) and 11 (21.6%) before interrupting VEN-AZA. Complete response with negative MRD was found for 24 out of the 28 evaluable patient (85.7%). Discontinuation of VEN and/or AZA treatments was based on physician choice because of hematological and/or non-hematological toxicities in 36 (71.6%) and 9 (17.6%) cases. Treatment interrupted was VEN, AZA or both in 26 (51%), 1 (2%) and 24 cases (47.1%), respectively. Median follow-up was 17.8 (15.2-20.4) months. Median EFS and OS were 16.7 (12.8-20.6) and 26.8 (14.1-39.5) months, respectively (Figure). Median duration of treatment-free remission (TFR) was 10.1 (7.1-13.1) months (Figure). Twelve patients resumed VEN and/or AZA treatment. For these patients, CRc, MLFS and SD/PD was obtained in 6 (50%), 2 (16.6%) and 5 (41.6%) cases. Obtaining a CR/CRi following the first VEN-AZA cycle and number of prior VEN-AZA cycles >4 were the main prognostic factors associated with a longer EFS and OS in univariate and/or multivariate analyses (Table). None of these factors were predictive for a better TFR, except the achievement of CR/CRi after cycle 1 (HR=2.2, p=0.05). The type of interrupted treatment (VEN versus VEN-AZA) did not influence EFS, OS nor TFS. Conclusion: Our findings confirm the high efficacy of VEN-AZA treatment in AML. Discontinuation of VEN and/or AZA treatment in responders was associated with durable responses and survival. Strategies of de-escalation based on clinical response, MRD and/or molecular profiling may be envisaged but will require a prospective evaluation in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epag 2015 : A Phase II Randomized Placebo-Controlled Study to Assess the Impact on Outcome of Eltrombopag Administered to Elderly Patients with Acute Myeloid Leukemia Receiving Induction Chemotherapy. a French Innovative Leukemia Organization (FILO) Study

Epag 2015 : A Phase II Randomized Placebo-Controlled Study to Assess the Impact on Outcome of Eltrombopag Administered to Elderly Patients with Acute Myeloid Leukemia Receiving Induction Chemotherapy. a French Innovative Leukemia Organization (FILO) Study

A Fixed-Duration Immunochemotherapy Approach Combined with Ibrutinib in CLL Produces Deep and Sustained MRD Responses: 5.5-Year Results from the Icll-07 Filo Trial

Introduction In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), the availability of targeted agents has led to research interest in achieving deep, durable remissions and improving survival outcomes. The phase II ICLL-07 (NCT02666898) trial by the French Innovative Leukemia Organization (FILO) evaluated a fixed-duration (15-month) immunochemotherapy approach (no more than 4 fludarabine/cyclophosphamide [FC]-obinutuzumab cycles). Primary analysis showed the approach was safe and 62.2% (84/135) of all patients enrolled achieved complete response (CR) with bone marrow (BM) minimal residual disease (MRD) <0.01% (Michallet et al Lancet Haematol 2019;6:e470-9). Follow-up at median 37 months from treatment start showed a persistent MRD benefit beyond end of treatment, high survival rates, and low long-term toxicity (Michallet et al Blood 2021;137:1019-23). Here we report long-term results at median 64 months from treatment start (data cut-off 20 May 2022). Methods Between 27 October 2015 and 16 May 2017, 135 previously untreated, medically fit patients with CLL were enrolled from 27 FILO centers. All received obinutuzumab 1000 mg (8 infusions over 6 cycles) plus ibrutinib (420 mg/day for 9 months). Following evaluation at D1 M9 (N=130 evaluable), those in CR with BM MRD <0.01% then continued only ibrutinib 420 mg/day for 6 additional months (I arm; n=10); otherwise, patients received 4 cycles of FC-obinutuzumab 1000 mg alongside continuing ibrutinib 420 mg/day for 6 additional months (I-FCG arm; n=115). Beyond end of treatment, patients were followed for peripheral blood (PB) MRD every 6 months, response every 3 months, progression-free/overall survival (PFS/OS), and safety. MRD was assessed by 8-color flow cytometry, using a highly sensitive (10-6) technique developed by the FILO group that enables subdivision of classical MRD <0.01% into low-level positive MRD <0.01% and undetectable MRD. Results At D1 M16, undetectable PB MRD rates were 80.0% (8/10) in the I arm and 92.5% (99/107) in the I-FCG arm. Beyond end of treatment, in the I arm the undetectable PB MRD rate decreased rapidly, and by M40 all patients had PB MRD positivity (≥0.01% or low-level positive <0.01%). In the I-FCG arm, the undetectable PB MRD rate was 76.3% (61/80) at M40, and of patients currently investigated at M64, 50/62 (80%) still had undetectable PB MRD (Figure 1). Four relapses occurred beyond end of treatment, including 2 CLL progressions (both Richter's syndrome). Throughout follow-up, no differences in undetectable PB MRD rates were apparent in the I-FCG arm according to the IGHV -mutated versus unmutated status (currently at M64: 20/27 versus 25/35, P=0.26). Overall 4-year PFS and OS rates (95% confidence intervals) were 95.5% (92% to 99 %) and 96.2% (93% to 99.5%), respectively. Of 12 deaths overall, 7 occurred beyond end of treatment, with 5 since last publication due to Richter's syndrome at M50, COVID at M50, lung cancer at M50, myelodysplastic syndrome at M60, and acute myeloid leukemia at M69. Other serious adverse events since last publication were metastatic prostate adenocarcinoma at M50 and suspicion of cerebrovascular accident at M65. Conclusion Long-term results from the ICLL-07 trial in previously untreated, medically fit patients with CLL demonstrated that that our fixed-duration (15-month) immunochemotherapy approach produced deep and sustained undetectable PB MRD responses that were correlated to PFS, without excess toxicity. These long-term MRD results remain the best to date even compared to the new targeted therapy combinations ie ibrutinib +veneteclax or obinutuzumab + venetoclax A randomized trial is needed to compare our approach with a chemotherapy-free strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Outcomes of Adult Patients with T Prolymphocytic Leukemia: A Real World Study of the French Innovative Leukemia Group (FILO)

Introduction T-prolymphocytic leukemia (T-PLL) is a rare T-cell neoplasm of aggressive clinical course and poor outcome. Treatment with the monoclonal antibody to CD52-alemtuzumab (alem) has considerably improved outcomes, yet with transient responses. Bendamustine (benda) showed encouraging results, particularly in alem-refractory patients (pts). Allogeneic hematopoietic stem cells transplantation (Allo-HSCT) has been reported to be effective in T-PLL, yielding durable remissions and improved overall survival (OS). New approaches using well-tolerated therapies and drugs that target such growth and survival signals as that the JAK/STAT pathways or BCL2 have recently been tested in small series of pts ineligible to intensive therapy. Methods The present multicenter study aimed at evaluating clinical and biological characteristics, as well as outcome of a cohort of 157 T-PLL pts over 18 years old (yo) treated in any of 24 centers of the French Innovative Leukemia Organization (FILO) between 03/1997 and 05/2022. OS, relapse, progression and progression-fee survival (PFS) were evaluated. Molecular analyzes searched for JAK1, JAK3, STAT5B, IL2RG, NOCH1, NOTCH2, EZH2, TET2 and TP53 mutations/deletions in 39 pts. Results Pts characteristics are shown in Table 1. The median age at first therapy was 72 yo (range 30-94). Neuro-meningeal and extra-nodal involvement were present at diagnosis and first relapse in respectively 4.6% / 10.5% and 5.9% / 14.3% of pts. At diagnosis, 12% of pts had hemoglobin <100 g/L, 32.6% thrombocytopenia <100x109/L and 43% lymphocytosis >40x109/L. Flow cytometric immunophenotyping showed pan-T antigens expression (CD2,CD3, CD5, CD7) in nearly all pts (table). Alpha-beta TCR was present for 64/73 pts (87.7%) and CD25 for 17/42 (40.2%). The TPLL was CD4+ for 73/98 pts (74.5%), CD8+ for 7/93 (7.5%), double positive (CD4+/CD8+) for 15/93 (16.1%) and double negative (CD4-/CD8-) for 3/92 (3.2%). Cytogenetics/FISH showed recurrent changes involving chromosome 14 in 69/95 (72.6%) pts [inv(14) and t(14;14) in 47/69 (68.1%) and 7/69 (10.3%)] and complex karyotype in 67/95 (70.5%). C-MYC gain, ATM and TP53 deletions/mutations were identified in respectively 22.6%, 27.5% and 16.4% of the pts analyzed at diagnosis, while JAK1, JAK3, and STAT5B were mutated in 15.4 %, 64.3% and 21.4% of tested cases. Additional results will be presented at the meeting. Pts received 1 to 5 lines of treatment (median 1). In first line, 45/127 (35.4%) evaluable pts received alem 30 mg IVx3 per week, after ramp-up (median:6 cycles; 1-10), with for 7 of them a previous sequence of benda (90 mg/m2 on day 1 [D1]). Thirty pts (23.6%) received first line benda 90 mg/m2 on D1 then 2x6 cycles every 28 days (median 3; 1-6), 15 (11.8%) received pentostatin, 11 (8.6%) had a CHOP-like regimen. Best supportive care was provided to 21 pts (16.5%). No treatment was proposed to 3 indolent pts (2.3%). Various schedules were applied to the remaining pts. Post-CR Allo-HSCT was performed for 20 pts (15.7%). Median follow-ups are 9.5 months (0.03-217) for the whole cohort (Figure1) and 11.8 (0.03-221) for Allo-HSCT recipients. Median OS are respectively 12.5 (8.4-17.5) and 23.2 months (5.82-not reached [NR]). The median PFS of the whole cohort is 2.6 months (0-217). Median OS for patients treated with alem or benda in first line are respectively 14.1 (8.4-25.4) and 7.8 (4.3-21) months, while OS for pts who had a benda bridge is 8 months (3.22-NR). The overall response rate (ORR) after first line is 42.7 % (CR 25.6%, partial response [PR] 17.1%). ORRs after first line alem or benda are respectively 53.5% (CR 41.9%, PR 11.6%) and 35.7% (CR: 14.3%, PR 21.4%). In univariate analysis, platelets<100x109/L (HR: 1.95 [1.28-2.95]; p=0.002%) and complex karyotype (HR: 2.08 [1.19-3.63]; p=0.010) statistically significantly appear to impact survival. Conclusion This large study demonstrates that alem therapy significantly improves the survival of T-PLL pts. Consolidation by Allo-HSCT should however be performed for all eligible patients achieving CR. Other therapeutic agents should be reserved for relapse. Prospective trials are needed to define the most effective therapeutic strategy and improve clinical responses to frontline therapy. New approaches using well-tolerated targeted therapies involving growth and survival signals are needed for the majority of patients unable to receive intensive chemotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dexaml-02 : A Phase II Study of Dexamethasone Added to Induction and Postremission Therapy in Older Patients with Newly Diagnosed AML. a French Innovative Leukemia Organization (FILO) Study

Background In a recent retrospective study, we have showed that the addition of dexamethasone to intensive chemotherapy was significantly associated with a better outcome in AML patients with hyperleukocytosis at diagnosis (Bertoli S, Haematologica 2018). Moreover, preclinical studies demonstrated that specific AML oncogenic alterations (RUNX1-RUNX1T1, RUNX1, NPM1, or SRSF2 mutations as well as NF-kB activation in leukemic stem cells) or therapeutic stress (cytarabine, FLT3 inhibitors) are associated with up-regulation of the inflammatory gene response and expression of the glucocorticoid receptor which induce sensitization to glucocorticoids (Récher C, Front Oncol 2021). Therefore, dexamethasone, used as a chemo sensitizer in combination with intensive chemotherapy, may improve treatment response and outcome regardless of the white blood cell count. Methods DEXAML-02 (LAM-SA 2018) is a non-randomized phase II multicenter trial to assess the impact on outcome of dexamethasone added to induction chemotherapy in older patients with AML (NCT03609060). Key inclusion criteria were: > 60 years of age, newly diagnosed AML (either de novo or therapy-related AML), favorable or intermediate cytogenetic risk according to MRC 2010 classification, ECOG performance status < 3; HCT-CI score < 3, adequate baseline organ function. Key exclusion criteria were: AML with adverse cytogenetic risk, AML arising from MDS, MPN or CMML, AML with BCR-ABL1, known active central nervous system leukemia. Induction chemotherapy regimen consisted in one cycle of idarubicin 8 mg/m²/day, D1 to D5, cytarabine 100 mg/m²/d, CIV D1 to D7, lomustine 200 mg/m²/d, orally at D1 and dexamethasone 10 mg/12h, IV, D1 to D3. The use of G-CSF, anti-fungal, anti-viral and anti-pneumocystis jiroveci prophylaxis were recommended. Patients who failed to reach complete remission (CR/CRi) after this single cycle of induction were off-study whereas CR/CRi patients were planned to receive up to 6 courses of mini-consolidation administrated every 30 to 45 days with idarubicin 8 mg/m², D1, cytarabine 50 mg/m²/12h, subcutaneous, D1 to D5, dexamethasone 20 mg/d, D1. The addition of midostaurin in patients with FLT3-ITD or FLT3-TKD mutations was allowed during induction, consolidation and maintenance. Allogeneic stem-cell transplantation was allowed after 2 to 4 cycles in patients with intermediate or adverse risk according to ELN 2017 classification. Patients with CBF-AML could receive 2-3 cycles of intermediate dose cytarabine (with dexamethasone) instead of 6 cycles of mini-consolidations according to investigator choice. Results From August 2018 to February 2020, 120 patients were included. 75 patients were male (62.5%). Median age was 70y (min-max, 61-80). Median WBC was 4.9 G/L (0.64-137). Most patients had an intermediate cytogenetic risk (91.7%). NPM1 and FLT3 mutations (per local analysis) were observed in 45 (37.5%) and 33 patients (27.5%), respectively. NGS of a 91 myeloid panel genes was centrally performed in 111 patients. 24 patients received midostaurin. Following the induction cycle, 100 patients (83.3%) achieved CR/CRi, 14 failed (11.7%) and 6 died early (5 %). In NPM1mut patients, 43 achieved CR/CRi (95.6%). During induction, grade III-IV adverse events were: infections (50.8%), mucositis (16.7%), gastro-intestinal (14.2%), hepatic (11.7%), hyperglycemia (10.8%), pulmonary (7.5%), cardiac (5.8%), cutaneous (5%) or bleedings (5%). Of the 100 CR/CRi patients, 86 entered the consolidation phase of whom 59 and 38 received 3 and 6 cycles, respectively. 23 patients received an allogeneic-SCT in first CR. The median follow up time was 31.4 months. Median RFS and OS were 20.2 and 30.7 months, respectively. In NPM1mut patients, median RFS was 20.1 months while median OS was not reached. Conclusion In older AML patients who are eligible for intensive treatment, adding dexamethasone to induction and consolidation chemotherapy is feasible and associated with a high response rate after a single induction cycle and encouraging overall survival. A historical comparison with the patient population of the LAM-SA 2007 trial (Pigneux A, JCO 2018) will be presented during the meeting to highlight a potential signal of activity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Response to vaccination against SARS‐CoV‐2 in 168 patients with Waldenström macroglobulinaemia: A French Innovative Leukaemia Organization study

Response to vaccination against <scp>SARS‐CoV</scp>‐2 in 168 patients with Waldenström macroglobulinaemia: A French Innovative Leukaemia Organization study

Prognostic Significance of DDX41 Germline Mutations in Intensively Treated AML Patients: An ALFA-Filo Study

Prognostic Significance of DDX41 Germline Mutations in Intensively Treated AML Patients: An ALFA-Filo Study

Preliminary Study of Ruxolitinib and Venetoclax for Treatment of Patients with T-Cell Prolymphocytic Leukemia Refractory to, or Ineligible for Alemtuzumab

Preliminary Study of Ruxolitinib and Venetoclax for Treatment of Patients with T-Cell Prolymphocytic Leukemia Refractory to, or Ineligible for Alemtuzumab

Humoral Response to mRNA Vaccines BNT162b2 and mRNA-1273 COVID-19 in Chronic Lymphocytic Leukemia Patients

Humoral Response to mRNA Vaccines BNT162b2 and mRNA-1273 COVID-19 in Chronic Lymphocytic Leukemia Patients

The French innovation funding programme (Article 51)

Abstract The “art 51” of the social security financing act was launched in 2018 and created an experimental framework to test a programme for healthcare delivery and payment innovation. Its aim is to fund projects that promote coordination, group practices, integration of care, through adequate payment mechanisms. Projects emerge from the field, identifying unmet needs and proposing innovative health care organisations and payment schemes. This presentation will provide insights into this new experience, into the obstacles and the lessons learned.

In-depth time-dependent analysis of the benefit of allo-HSCT for elderly patients with CR1 AML: a FILO study

AbstractThe benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) aged >60 years remains a matter of debate, notably when performed in first complete remission (CR1). To clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN) 2010 classification. The impact of allo-HSCT was analyzed through three models: (1) time-dependent Cox; (2) multistate for dynamic prediction; and (3) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR patients with AML, 203 of whom received an allo-HSCT. Classical multivariate analysis showed that allo-HSCT significantly improved relapse-free survival (RFS; hazard ratio [HR] [95% confidence interval (CI)], 0.47 [0.35-0.62]; P < .001) and overall survival (OS; HR [95% CI], 0.56 [0.42-0.76]; P < .001), independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without allo-HSCT continue to relapse over time. Finally, the super landmark model showed that allo-HSCT significantly improved RFS (HR [95% CI], 0.47 [0.36-0.62]; P < .001) and OS (HR [95% CI], 0.54 [0.40-0.72]; P < .001). allo-HSCT in CR1 is reported here as significantly improving the outcome of fit older patients with AML. Long-term RFS without allo-HSCT is very low (<10%), supporting allo-HSCT as being the best curative option for these patients.

The Bendamustine Plus Rituximab Regimen Is Active and Safe in Previously Untreated Patients with Waldenström Macroglobulinemia, a Study on Behalf of the French Innovative Leukemia Organization (FILO)

BackgroundWaldenström macroglobulinemia (WM) is a rare low-grade B-cell malignancy characterized by the infiltration of IgM-secreting lymphoplasmacytic cells in the bone marrow. There is no standard therapy for WM, but several drugs have been shown to be effective either alone or in combination. Bendamustine (B)-Rituximab (R) has been found to be effective in salvage (Tedeschi , Leukemia Lymphoma 2015) or first setting in MW (Treon, ASH2016).BR- regimen has however reported to be associated with an increase in secondary cancer and the development of secondary myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) in patients with previously treated non-Hodgkin lymphoma. Prolonged neutropenia after R-chemotherapy treatment of lymphoma or CLL has also been associated with an increase of MDS/AML, and a shorter interval between the occurrence of the two malignancies. However, this has not been evaluated in previously untreated WM, nor the possible relationship with secondary cytopenia to WM treatment.MethodsForty-four symptomatic previously untreated patients with WM based on the second WM Workshop recommendations for diagnostic criteria were enrolled in this retrospective multi-center study between January 2012 and January 2017 in ten French centers. MYD88L265P and CXCR4 mutations were searched using q PCR and or next generation sequencing. Del (17) p and/ or TP53 mutation were investigated for 22 patients. All patients received a BR regimen consisting of 375 mg/m2 of rituximab on day 1 and 90 mg/m2 of bendamustine on days 1 and 2, repeated every 4 weeks, with a maximum of 6 cycles. Long-term complications of BR, 6 months or more after treatment discontinuation were analyzed. PFS and OS were plotted using the log rank test and Kaplan-Meier comparison.ResultsThe median age at WM diagnosis was 69 years old (range 45-88) and the median age at initiation of therapy was 70 years old (range 46-89). The MYD88L265Pmutation was present in 24/30 (80%) of the cases. CXCR4 mutations were observed in 2/14 cases, alteration of TP53 in 1/22 cases.The median time from diagnosis to therapy was 2 months (range 0-123 months). The median serum IgM level was 3,870mg/dl (range 650-12000). The criteria for initiating BR treatment were: anemia (54%), B-symptoms (45%), hyper viscosity (25%), adenopathy and/or splenomegaly (18%), thrombocytopenia (16%), neuropathy (11%), and amyloidosis (4%). According to the IPSSMW score, 22% of patients were low risk, 35% intermediate risk, and 43% high risk. Overall 82% of patients completed the planned 6 courses.Using consensus response criteria, the ORR was 95% (CR15%, VGPR 40% PR38% MR 2%) and the major response rate (CR+VGPR+PR) 93%.Toxicities attributed to BR led to dose reduction and/ or incomplete regimen of intended therapy in 18% of patients. Their median age was 78 years old. Toxicities were related to excessive or prolonged myelosuppression in 5 patients and infection in 3.Most of the adverse events were hematological and infectious toxic effects. Grade 3-4 neutropenia occurred in 4 (11%) cases and grade 3-4 thrombocytopenia in one (3%). Minor infections developed in eight cases: three cutaneous infections, two herpes zosters, one upper respiratory tract infection, one sinusitis, and one oral-herpes. Grade 3-4 pneumonia was observed in two cases and sepsis in one.Among 38 evaluable patients for toxicities after BR therapy, 16(42%) developed one or more long-lasting cytopenias: neutropenia (34%), anemia (10%), and thrombocytopenia (8%), all grade I and II.The median duration for prolonged neutropenia, anemia, and thrombocytopenia were 6 months (range: 6-24 months), 7.5 months (range: 6-9 months) and 12 months (6-30 months), respectively.After a median observation time of 27 months (range 5-51 months) after BR-regimen, the PFS and OS were 92% and 100%, respectively. Two patients relapsed at 24 and 45 months. One patient with a history of breast cancer prior to WM treatment relapsed from this solid tumor at 23 months. None of the patients developed aggressive lymphoma or secondary MDS/AML at the last follow-up.ConclusionThe BR regimen is efficient in patients with previously untreated WM. In elderly patients, the dose of bendamustine needs to be lowered. Long-lasting cytopenia occurred in half of patients and resolved in most cases within one year after the end of treatment. Longer follow-up is needed to assess the long-term risks of BR treatment. DisclosuresLaribi:MUNDIPHARMA: Research Funding; NOVARTIS: Honoraria, Research Funding; ROCHE: Research Funding; TEVA: Research Funding; HOSPIRA: Research Funding; AMGEN: Honoraria; TAKEDA: Honoraria, Research Funding. Leblond:SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees.