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  • 1
    In: Annals of Hematology, Springer Science and Business Media LLC
    Abstract: We conducted an observational study (FIRE) to understand the effectiveness and safety outcomes of ibrutinib in patients with chronic lymphocytic leukemia (CLL) in France, after a maximum follow-up of five years. Patients were included according to the French marketing authorization in 2016 (i.e. patients with relapsed or refractory CLL or to previously untreated CLL patients with deletion 17p and/or tumor protein p53 mutations unsuitable for chemoimmunotherapy) and could have initiated ibrutinib more than 30 days prior their enrolment in the study (i.e. retrospective patients) or between 30 days before and 14 days after their enrolment (i.e. prospective patients). The results showed that in the effectiveness population ( N  = 388), the median progression-free survival (PFS) was 53.1 (95% CI: 44.5–60.5) months for retrospective patients and 52.9 (95% CI: 40.3–60.6) months for prospective patients and no difference was shown between the PFS of patients who had at least one dose reduction versus the PFS of patients without dose reduction ( p  = 0.7971 for retrospective and p  = 0.3163 for prospective patients). For both retrospective and prospective patients, the median overall survival was not reached. The most frequent treatment-emergent adverse event of interest was infections (57.6% retrospective; 71.4% prospective). A total of 14.6% of the retrospective patients and 22.4% of the prospective patients had an adverse event leading to death. Our findings on effectiveness were consistent with other studies and the fact that patients with dose reductions had similar PFS than patients without dose reduction is reassuring. No additional safety concerns than those already mentioned in previous studies could be noticed. Trial registration  ClinicalTrials.gov, NCT03425591. Registered 1 February 2018 – Retrospectively registered.
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
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  • 2
    In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 108, No. 10 ( 2023-04-20), p. 2774-2782
    Abstract: Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37–82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3–12). The median number of BM cycles administered was three (range, 1–22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.
    Type of Medium: Online Resource
    ISSN: 1592-8721 , 0390-6078
    Language: Unknown
    Publisher: Ferrata Storti Foundation (Haematologica)
    Publication Date: 2023
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3781-3781
    Abstract: Abstract 3781 Background. We have reported the results of imatinib discontinuation in CML pts in complete molecular response (CMR) for more than 2 years under imatinib therapy (STIM study, Mahon et al. Lancet Oncol. 2010). Among the group of pts without confirmed molecular relapse, a small proportion exhibited low levels of detectable residual disease during a prolonged period of time. Aims. In order to better characterize this phenomenon, we decided to analyse pts who stopped IM following a maintained CMR or an undetectable molecular residual disease (UMRD) and resumed therapy upon loss of major molecular response (MMR). We also aimed to validate the loss of MMR as a robust criterion for the re-introduction of tyrosine kinase inhibitors (TKIs). Patients and methods. CP-CML pts were eligible if they were in CMR (CMR4.5: BCR-ABL/ABL IS ratio 〈 0.0032%) or UMRD (undetectable Bcr-Abl using standardized RTQ-PCR) under imatinib therapy for more than 2 years. Those pts were not enrolled in the STIM study because the study was closed or because they experienced at least one positive value of the BCR-ABL/ABL ratio during the 2 years follow-up. The proposed criterion for resuming imatinib was the loss of MMR (BCR-ABL/ABL IS ratio 〉 0.1%). We calculated relapse free survival (RFS) using three different end-points: First loss CMR/UMRD defined by one occurrence MRD positivity; second loss of CMR/UMRD using the STIM definition (two consecutive increasing values of MRD); third loss of MMR. We also described pts with long lasting fluctuating PCR values. Results. 34 CP-CML pts were included in the analysis. Median follow-up after imatinib discontinuation was 21.3 months (2.2–83.1). Sex ratio (M/F) was 50% with a median age of 54.1 years (27.4–78.2). Sokal score distribution was 34.5%, 37.9% and 27.6% for low, intermediate and high values respectively. 19 out of 34 (55.9%) of the pts received interferon therapy prior to imatinib. Median duration of imatinib therapy and median duration of CMR/UMRD prior to discontinuation was 63.8 months (30.1–120.8) and 33.7 months (7.3–72.8) respectively (only two pts had CMR/UMRD duration less than 2 years). Of note 18 out of 34 pts (52.9%) had a least one MRD positive value after the achievement of CMR/UMRD. After imatinib discontinuation, we identified 11 pts (32.4%) who experienced repeated low levels of detectable MRD without losing their MMR. Median follow-up for these pts with fluctuating values of MRD was 15.4 months (3.5–59.5) and none of them restarted imatinib. We next analysed relapse free survival (RFS) using the loss of MMR criteria (RFS-MMR). Median RFS-MMR was not reached, compared to median RFS using the loss of CMR/UMRD criteria (4.8 months) and median RFS using the STIM criteria (13.8 months) (p=0.003). As a consequence, 62.8% of the pts remain treatment free at 2 years using the loss of MMR criteria for resuming imatinib. Fluctuating values of MRD has already been described after interferon cessation in CML interferon treated pts. We thus asked if prior therapy with interferon before imatinib may influence treatment free survival. Duration of imatinib therapy and Sokal score risk distribution were comparable between pre-treated and non pre-treated pts (p=0.7). However, the median RFS was longer in interferon pre-treated pts as compared to pts who received imatinib first line (not reached versus 7 months, p=0.047). Furthermore, this difference was not significant using the loss of CMR/URMD (p=0.27) to define molecular relapse. Conclusions. We were able to identify a significant number of pts with fluctuating values of MRD after imatinib discontinuation, a proportion underestimated in previous studies. We also validated the loss of MMR as the most accurate and robust criteria for restarting imatinib after imatinib discontinuation. Applying this criterion, we demonstrated that treatment free survival is significantly better in pts previously treated with interferon before imatinib compared to pts who received imatinib as first line therapy. An update of this pilot study on a larger number of patients will be presented. Disclosures: Rousselot: BMS, Novartis: Research Funding. Tulliez:Novartis:. Mahon:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Pfizzer: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3193-3193
    Abstract: Background Advanced Systemic Mastocytosis (adSM) still have very poor prognosis. No standard of care is yet available. Midostaurin (PKC412) is a powerful TKI inhibit of VEGFR, FLT3 and most importantly the mutated CKITD816V and D816Y. Preliminarily results from an international phase II trial (Gotlib et al., Blood 2012) reported interesting results in this subgroup of patients. We report herein on the French experience of the compassionate use of PKC412 for the treatment of adSM and compare their outcome to matched adSM historical control patients (pts) who did not receive PKC412 (control group). Methods Over a period of 12 months (from August 2012, date of PKC412 Temporary Approval for Use in France), 22 pts received PKC412 and could be analysed. PKC412 100 mg twice daily was administered orally as continuous 28-day cycles until progression or unacceptable toxicity. Pts were evaluated according to the response criteria used in the recent phase 2 trial on midostaurin (Gotlib et al.). The overall survival (OS) of these 22 patients was compared to the OS of 42 age and WHO subcategories matched control adSM patients who were treated before PKC412 era. Results 2 female and 20 male pts with a median age of 65 years [35-84] received midostaurin. Overall, 21 pts (95%) with adSM (5 ASM; 2 MCL; 1 MCS; 12 ASM-AHNMD; 1 SSM-AHNMD,1) and 1 pt progressive SSM. Median number of C-Findings was 3 (0-4). Hepato- and/or splenomegaly were present in 20 (91%) and 21 (95%) pts. Median tryptase level was 204 ng/l (85-2000). Median haemoglobin level, platelet and PMN counts were respectively 10.1g/dl (6.8-13.9), 117G/L (22-289) and 2.8G/L (0.3-17). Twenty (91%) pts had cKIT D816V mutation, 2 pts had cKITWT. ASXL1 and TET2 were mutated in 3/7 and 2/7 tested, respectively. Steroids, 2-chlorodeoxyadenosine and Interferon were administered in 9, 4 and 2 pts prior to midostaurin. After a median exposure time of 6.9 [1.6-27.5] months, the overall response rate (ORR) was 77.2% including, major responses (n=13; 59%) (incomplete major in 8 pts, pure clinical in 5); partial response (n=5, 23%) (good partial in 3, minor partial in 2). Three patients were rapidly progressive ( 〈 2 months) and considered refractory to PKC412 (1 MCL, 1 MCS, 1 ASM-AHNMD). Death occurred in 4 pts (refractoriness 2 pts, AHNMD progression 2 pts). After a median follow-up of 7.4 months from PKC412 start, median OS was 24.4 months [12.6-34.2]. Patients with ASM seemed to better benefit from PKC412, however, no significant difference was found between the ASM and SM-AHNMD, probably due to the low patient’s number. The control group consisted in 42 pts with a median age of 65.5 years [23-84]. There were 17 ASM-AHNMD, 21 ISM-AHNMD, 2 SSM-AHNMD, 1 CM-AHNMD and 1 MCL patients. Median tryptase level was 107ng/l [19-501] . Median haemoglobin level, platelet and PMN counts were respectively 12.1g/dl [8-15], 200G/L [10-1036] and 4.6G/L [0.5-24.3]. Thirty-three (79%) pts had cKIT D816V mutation, 7 pts were cKITWT. ASXL1 and TET2 were mutated in 6/29 (21%) and 7/29 (24%) of pts tested, respectively. Steroids, 2-CdA, interferon, imatinib, thalidomide have been used in 19, 21, 6, 4, and 6 pts respectively. Survival distributions were estimated using the adjusted Kaplan-Meier method from the date of diagnosis to the last follow-up for the PKC412 treated and the control groups. Median survival time for PKC412 treated patients was significantly longer than control patients (p=0.04). Conclusion PKC412 is active in advanced SM. Despite the absence of complete remission, PKC412 gives survival advantage for patients with adSM over pts who did not receive the drug. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 5
    In: European Radiology, Springer Science and Business Media LLC, Vol. 31, No. 5 ( 2021-05), p. 2944-2955
    Type of Medium: Online Resource
    ISSN: 0938-7994 , 1432-1084
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 6
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 381-381
    Abstract: More than half of patients with chronic phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and methods A multicenter observational study (A-STIM, According to STop IMatinib) evaluating MMR persistence was conducted in 80 CP-CML patients who had stopped imatinib after prolonged confirmed CMR (24 months or more). Patients with confirmed CMR with 1 or 2 occasional weak positive samples before study entry were also considered eligible. CMR was defined as undetectable BCR-ABL transcript with a sensitivity of at least 40000 amplified copies of the ABL control gene, in accordance with the level of sensitivity routinely applied within laboratories participating in the French GBMHM Network. Results Median time from imatinib initiation to discontinuation was 79 months (range 30-145), median duration of CMR before imatinib discontinuation was 41 months (24-96), and median follow-up after discontinuation was 31 months (8-92). Twenty-nine patients (36%) lost MMR after a median of 4 months off-therapy (2-17). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25%-46%) at 12 months and 36% (95% CI, 26%-47%) at 24 months whereas probability of losing CMR was estimated as 51% at 12 months (95% CI, 41%-63%) and 54% at 24 months (95% CI, 44%-66%). Fivety two percent of the patients met the criteria for cCMR but experienced occasional BCR-ABL positivity (unstable cCMR). Those patients were not at higher risk of losing MMR as compared to patients with stable cCMR. This observation may potentially increase by two-fold the number of patients eligible for TKI discontinuation. Fluctuation of BCR-ABLtranscript levels below the MMR threshold (≥ 2 consecutive positive values) were observed in 31% of patients after imatinib discontinuation. Using cell sorting in three fluctuating patients, we were able to confirm that BCR-ABL signal was mostly present in the CD15 positive fraction, demonstrating first that BCR-ABL residual signal was not related to long living lymphoid cells and second that residual CML cells retain a clonogenic potential. Treatment-free remission was estimated as 64% (95% CI, 54%-75%) at 12 and 24 months and 61% (95% CI, 51%-73%) at 36 months. Treatment was resumed in 31 patients after loss of MMR. Twenty-three patients regained CMR4.5 and 8 patients are in MMR under therapy after 2+ to 17+ months. Median to time to a second CMR was estimated as 7.3 months in retreated patients. Conclusion The probability of losing MMR after imatinib discontinuation was estimated as 36% in the long-term. Loss of MMR is a practical and safe criterion for restarting therapy in CML patients with prolonged CMR and could be used for future discontinuation studies. Disclosures: Rousselot: Novartis: Research Funding; BMS: Research Funding. Cony-Makhoul:BMS: Honoraria; Novartis: Research Funding. Nicolini:BMS, Teva, Ariad, Pfizer, Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy; Pfeizer: Consultancy; Novartis: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees. Turhan:BMS: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding. Guilhot:BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Novartis: Research Funding. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4206-4206
    Abstract: Introduction: in large unselected series, the median age of Primary CNS Lymphoma (PCNSL) patients (pts) is about 70 years. In one USA cancer registry study for PCNSL patients (pts) older than 65 years, 14% of them are older than 80 years. Data on clinical characteristics, therapeutical management, toxicity of treatment and outcome of these very elderly pts are limited. Methods: We reviewed PCNSL pts aged of 80 years or older included in the database of the French Oculo-Cerebral lymphoma (LOC) network. From January 2011, this network prospectively recorded all newly diagnosed PCNSL from 22 regional expert centers in France. For this study, 110 PCNSL pts with a histological diagnosis of diffuse large B-cell lymphoma (DLBCL) aged of 80 years or older were analyzed. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities and outcome. Results: 110 pts with a DLBCL PCNSL aged of 80 years or older were diagnosed between January 2011 and January 2018 representing 8% of pts available in the LOC database. The clinical characteristics were as follows: 63% of females; median age: 83y (80-92); performance status (PS) according to EORTC scale: 1, 24% of pts, 2, 21% of pts, 3-4, 55% of pts. 23.6% of pts had a CIRS-G grade 3 or 4 in at least one category and 40.9% had a cumulative CIRS-G score more than 6. Diagnosis procedure was biopsy (87%), tumor resection (5%), vitrectomy (4%), CSF cytology (4%). At diagnosis, 9/68 (13%) of evaluable pts had ocular involvement, 13/61 (21%) cerebrospinal (CSF) involvement, 79/110 (72%) involvement of the deep structures of the brain and 35/86 (41%) had elevated LDH level. Median creatinine clearance (CKD.EPI) was 70ml/min (min: 24, max: 102). Treatment was initiated either by a neuro-oncology or a hematology team in 35% and 65% of cases, respectively. Median delay between first symptoms and treatment was 60 days. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) in 85 pts (77%), other chemotherapy regimen in 13 pts (12%) and palliative care in 12 pts (11%). Median number of CT cycles was 3 (1-11) with a median dose of MTX of 3g/m2 (0.5-5.0). Interestingly, no difference of distribution for the main clinical and biological characteristics (median age, PS, symptoms, tumor localization, albumin level, creatinine clearance) was observed between these three groups. Rituximab was used in combination with CT in 53/98 treated pts (54%). After first-line induction chemotherapy, response rate for evaluable patients (n=85) were as follows: 37% of complete response, 9% of partial response, 54% of stable or progressive disease. Finally, 27 pts (32%) received consolidation treatment with high-dose cytarabine after MTX-based CT. For toxicity, among the 351 infusions performed for the 85 pts who received MTX-based CT, grade 3-4 toxicities were: 46% of any events, 15% of infection, 13% of cytopenia, 10.5% of acute renal failure and 8% of elevated liver enzymes. 13% of pts presented toxic death. Median progression free survival (PFS) and overall survival (OS) were 3.9 months and 7 months, respectively. Pts treated with MTX-based CT had a significantly prolonged PFS and OS as compared to patients treated without MTX or with palliative care (Figure 1A, 1B). In the univariate analysis performed for the 85 pts treated with MTX-based CT, no initial clinical and biological characteristics (age, PS, type of symptoms, CIRS-G, tumor localization, LDH level, albumin level, hemoglobin level, lymphocyte count, creatinine clearance) influenced PFS or OS. The initial dose of MTX did not influence outcome but intravenous rituximab used in first line therapy significantly improved PFS and OS (Figure 1C, 1D). Conclusions: to the best of our knowledge, this is the largest series of consecutive PCNSL pts aged of 80y or over prospectively recorded in a national database. This study showed that the prognosis remains poor with major toxicity under conventional treatment. No clinical predictor of survival was highlighted in our series but patients initially treated with MTX-based CT in combination with rituximab had an improved outcome. The development of target and innovative therapies is needed for this category of patients representing 8% of all PCNSL in the database of the LOC network. Disclosures Houot: Celgene: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Novartis: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 8
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 15-16
    Abstract: Background: AcSé Pembrolizumab is a Phase 2, open-label, single-arm, multi-cohort, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with advanced rare cancers (NCT03012620). Here, we report the first results of Pembrolizumab in the cohort of Primary Central Nervous System Lymphoma (PCNSL). Methods: Main inclusion criteria were: relapsed or refractory PCNSL after one or several lines of treatment including high dose Methotrexate based chemotherapy, pathologically confirmed diffuse large B cell lymphoma, age & gt;18, HIV negative, concurrent steroid medication at a dose no greater than prednisone 20 mg/day or equivalent. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycles for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to IPCG at 84 day after the start of treatment. Secondary endpoints included best response (ORR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Analysis used all enrolled patients. Results: 50 patients suffering from PCNSL, including 9 primary vitreoretinal lymphoma (PVRL) were included from July, 2017 to October, 2019. Median age was 72 years (range: 43 to 83), Median PS (ECOG) was 1 (range 0-1). The median number of cycles was 4 (range 1-35). At 84 days from start of treatment, 6 patients responded (4 CR+2PR). Overall, 3 patients whose response was not assessed were considered as failures, and the rates of ORR (CR+PR), stable disease (SD), progressive disease (PD) were 26% (13/50, 8 CR + 5 PR), 10% (5/50), 58% (29/50), respectively. ORR was 29% (12/41) and 11% (1/9) in primary cerebral lymphoma and PVRL respectively. After a median follow-up of 6.7 months (range 0.2-27.4), median PFS was 2.6 months, with 6-month PFS of 29.8% and 6-month OS of 60.4%. In responders, median duration of response was estimated at 10 months (95%CI, 2.7 to 12.5). Grade III and IV toxicities related to the drug were observed in 4 patients (8%) and one patient (2%) respectively. No related toxic death was reported. Conclusion: Pembrolizumab shows moderate activity in relapsed/ refractory PCNSL with acceptable toxicity, supporting further studies evaluating its use in combination therapies. Disclosures Hoang-Xuan: BTG: Consultancy, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Ahle:Roche: Honoraria; Novartis: Honoraria; Biogene: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria. Bories:Abbvie: Consultancy; Celgen: Consultancy; Gilead: Consultancy; BMS: Honoraria; Novartis: Honoraria. Houillier:BTG: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 9
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 172-172
    Abstract: Abstract 172 Background. Dasatinib (Sprycel®) is a potent inhibitor of BCR-ABL and SRC family kinases. Based on the rapid and clinically meaningful activity observed when dasatinib was used as a single agent a consensus has been reached by the EWALL (European Working Group for Adult ALL) to conduct an international study evaluating the combination of dasatinib and low-intensity chemotherapy in patients with Ph+ ALL aged 55 years or more. Patients and Methods. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, dasatinib was administered at 140 mg QD (100 mg in patients over 70y) during the induction period in combination with IV injections of vincristine 1 mg and dexamethasone 40 mg 2 days (20 mg over 70y) repeated weekly for 4 weeks. Consolidation cycles consisted of dasatinib 100 mg/d administered sequentially with methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and L-asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of dasatinib alternating with 6-MP and methotrexate orally every other month and dexamethasone/vincristine once every 2 months for up to 24 months. Patients were molecularly monitored by a central laboratory for BCR-ABL RTQ-PCR and T315I resistance mutation ASO RTQ-PCR. Results. Seventy one patients were included from August 2007 to study termination in May 2010. Median age was 69.1 years (range: 58–83). Median follow-up was 16.3 months. At diagnosis, the Ph chromosome was associated with other abnormalities (complex, -7, Ph duplication or others) in 64.5% of cases. The CR rate after induction was 90% and 55.7% of the patients achieved a BCR-ABL/ABL ratio ≤0.1% at the time of CR. Failure to achieve CR was mainly related to death (n=5.7%). Serious adverse events (SAEs) during induction were infections (11%), elevated transaminases (7%), hemorrhage (5.6%), renal failure due to tumor lysis syndrome (4.2%) and cardiovascular events (5.6%). Only 2 pleural effusions were observed. During consolidation and maintenance, most frequent SAEs were infections (33.3%). One pleural effusion was observed. Nineteen patients relapsed after a median response duration of 19.2 weeks and 12 of them died. Thirteen patients presented mutations in the BCR-ABL TK domain at relapse (12 T315I, 1 F317L), no mutation was detected in 3 patients and results are pending in 3 patients. T315I ASO RTQ-PCR analysis during follow-up was predictive for relapse. The rise of the T315I signal over 0.1% was always associated with relapse and occurred 1 to 3 months before relapse in 6 of the 12 T315I cases and concomitantly in the 6 remaining patients. Four patients received RIC allogenic stem cell transplantation and were censored at the time of SCT. Median RFS and OS were 22.1 and 27.1 months, respectively. Cytogenetics findings at diagnosis were good predictors for RFS: the median RFS for patients with isolated Ph was not reached while it was 19.2 months in patients with additional cytogenetic abnormalities (p=0.03)). Molecular BCR-ABL transcript level after induction had no effect on RFS. However, a BCR-ABL ratio ≤0.1% after induction and then confirmed during consolidation was significantly associated with a better RFS (5.1 months versus not reached, p=0.006). Conclusions. Dasatinib combined with low-intensity chemotherapy is highly effective in elderly patients with Ph-positive ALL with a 90% CR rate and a 22.1 months RFS. Cytogenetics at diagnosis is a strong predictive factor for RFS. Most relapses were associated with the T315I mutation. Serial monitoring for T315I allowed us to predict for hematological relapse and may offer an opportunity to adapt therapy before relapse. Disclosures: Rousselot: Bristol Myers Squibb: Research Funding. Off Label Use: Dasatinib as first line therapy in Ph ALL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 10
    In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 57, No. 6 ( 2022-06), p. 966-974
    Type of Medium: Online Resource
    ISSN: 0268-3369 , 1476-5365
    RVK:
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 632854-4
    detail.hit.zdb_id: 2004030-1
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