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In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 102, No. 5 ( 2017-05), p. e184-e186

Type of Medium: Online Resource

ISSN: 0390-6078 , 1592-8721

URL: Article

DOI: 10.3324/haematol.2016.159905

Language: English

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2017

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detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 895-895

Abstract: AS2O3 has shown great promise in the treatment of patients with relapsed/refractory APL. We evaluated the results of an As2O3 (Trisenox®)-based treatment strategy proposed to French patients with relapsed APL over the last few years and compared these results to those of our previous strategy combining ATRA with EMA (etoposide + mitoxantrone + AraC) intensive timed-sequential chemotherapy (Thomas et al., Leukemia14:1006, 2000), particularly in the setting of hematopoietic stem cell transplantation (HSCT). 28 consecutive patients (median age, 52 years; range, 21 – 80) with relapsed (relapse 1, R1 = 22 of whom 2 in molecular relapse; R2, R3 or R4 = 6) APL (25 M3, 3 M3v) were treated with AS2O3 between 2002 and 2005. The time from the last complete remission (CR) was 20.5 months (range, 0.9 – 74). Initial treatment was AS2O3 (0.15 mg/kg/day iv) administered alone (n = 25) or combined with ATRA (n = 3) ± idarubicin (n = 1) until CR. Median time to CR was 47 days. Severe toxicities included infection (24%) and APL differentiation syndrome (20%). Median time for granulocytes & gt; 0.5 x 109/l was 15 days (range, 0 – 52). 24 patients (86%) achieved CR after initial AS2O3 treatment. Early death was observed in 2 cases and resistance in 2. CR was followed in 11 patients by at least a second cycle of AS2O3 ± consolidation chemotherapy + maintenance therapy (including ± AS2O3 ± ATRA). The 13 other remitters received HSCT (median time to transplant, 4.7 months): 9 underwent unpurged autologous SCT and 4 genoidentical allogeneic SCT, after at least a second cycle of AS2O3 ± one course of consolidation chemotherapy (n = 5). At a median follow-up of 2.5 years, 22 patients are alive. 4 (16%) have relapsed (median time to relapse, 8.1 months). 80% of patients in continuous CR were PML-RARα negative on sensitive nested RT-PCR. Median LFS was not reached. AS2O3-based therapy resulted in a 2-year LFS of 84%. 2-year OS was 73%. Prognostic factors were HSCT as postremission therapy (p = 0.01) and less than 3 therapeutic lines (p = 0.002). While CR proportions were comparable, 2-year LFS (84% vs 47%) and 2-year OS (79% vs 51%) increased in patients receiving AS2O3-based therapy as compared to the historic control. Severe infections were significantly lower with AS2O3-based regimen (24% vs 54%). When considering only patients receiving HSCT, results showed a benefit with AS2O3-based regimen in terms of 2-year LFS (100% vs 54%) and 2-year OS (100% vs 61%), the historic control showing a high mortality associated with the allogeneic SCT procedure. Our data shows that AS2O3-based therapy induces durable remission in a high proportion of patients with relapsed APL with no major toxicity. The results appear more favorable than those of our previous therapy based on ATRA and intensive timed-sequential chemotherapy particularly in the setting of HSCT. Combination AS2O3 and HSCT regimens are anticipated to further extend survival in relapsed APL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.895.895

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1444-1444

Abstract: Introduction. AML standard intensive induction chemotherapy ("3+7" or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity. Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex. Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p 〈 0.001). Ten days after FMT administration (S3), the Simpson index returned to its initial baseline level (0.50 to 0.86; p 〈 0.001). In addition to variations of the diversity, we demonstrated using the Bray-Curtis dissimilarity index (BC) a profound shift in the microbial communities following IC (mean BC S1-S2: 0.76) and the restoration of the initial microbial profile after FMT (mean BC S1-S3: 0.40). Moreover, IC and associated antibiotic treatments induced a significant increase in the mean number of readouts mapped against antibioresistance genes at S2 (167546 to 371466 reads, p 〈 0.01) that reflect ARGC. Then, a significant reduction of 43% of the mean number of reads mapped was observed at S3 after FMT (211128 reads, p 〈 0.001). No serious adverse events (SAE) were observed within 30 days after FMT and all post FMT SAEs were not related to the FMT procedure. Moreover, FMT did not induce any local or systemic inflammatory reaction as measured by fecal and blood markers (fecal neopterin and IgA; plasmatic CRP, IL-6 and sCD14). Interestingly, restoration of the microbiome diversity was associated with a significant reduction of CRP and fecal neopterin levels, suggesting a potential anti-inflammatory impact of FMT. Overall, FMT was well tolerated and had an excellent safety profile. The one-year overall survival estimate in the whole cohort was 84% (4 deaths among 25, none of which were related to FMT: 2 multiple organ failures, 1 heart attack and 1 grade IV resistant GVHD). The median time to death from the second FMT was 182.5 days (113-225 days). Conclusions. This is the first prospective trial testing the safety and efficacy of FMT in AML patients receiving intensive induction chemotherapy. The trial achieved its primary endpoint and established the capacity of FMT to restore a diverse microbiome with high levels of similarity to baseline, as well as reducing ARGC and intestinal inflammation. A controlled randomized trial with repeated FMT administrations is currently planned to further evaluate the impact of FMT on clinical outcomes and long-term survival. (This trial was funded by MaaT Pharma whose product was tested in this protocol). Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Doré:MaaT Pharma: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-112825

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 31-31

Abstract: Background. Tyrosine kinase inhibitors (TKI) are standard front-line therapy for patients with BCR-ABL1/Philadelphia positive ALL (Ph+ ALL), but the relative merits of available TKIs remain uncertain. Nilotinib is a potent inhibitor of BCR-ABL1 with broader activity against ABL kinase domain mutations than imatinib and greater selectivity than dasatinib or ponatinib. As there is a paucity of data on nilotinib as first-line therapy for Ph+ ALL, the EWALL (European Working Group for Adult ALL) conducted an international clinical trial to evaluate efficacy and safety of the combination of nilotinib with low intensity chemotherapy. Patients and Methods. After a prephase with dexamethasone (DEX) and cyclophosphamide, nilotinib (400 mg BID) was given concurrently with the same chemotherapy backbone employed in the EWALL-PH01 assessing the combination with dasatinib (Rousselot et al, Blood 2016;128:774-82). Induction consisted of nilotinib combined with weekly vincristine (VCR, 1mg iv) and oral dexamethasone 40mg 2 days (20 mg over 70y). Nilotinib was continued throughout six consolidation cycles, followed by 24 months maintenance therapy with nilotinib, 6-MP, MTX and DEX/VCR boosts. Stem cell transplantation (SCT) was permitted as considered appropriate. BCR-ABL1 RTQ-PCR and kinase domain resistance mutations were centrally monitored. Primary endpoint was event-free survival (EFS) at 12 months, secondary endpoints included rates of CR, major and complete molecular response, relapse free survival (RFS), EFS and overall survival (OS). Results. 72/79 enrolled pts. were evaluable for response, 3 withdrew consent, 4 did not meet eligibility criteria. Median age was 65.5 (55-85) years, male/female ratio 0.85, ECOG status 0 or 1 in 89% of pts., median CIRS comorbidity score 5(0-19). Baseline vascular risk factors including high blood pressure (grade ≥2) were present in 36% of pts.. Sixty-eight of 72 pts. (94.4%) achieved CR, one died during induction and one was refractory, 2 pts. discontinued study therapy. Non-hematologic adverse events (AE) grades 3/4 during induction (in ≥ 5% of pts. irrespective of causality) included infections (n=20), elevated transaminases or bilirubin (n=18) and gastrointestinal AEs (n=12). The spectrum of AEs was similar during consolidation, without concerns related to cardiovascular events. 24 pts. (61y; 55-69y) underwent allogeneic (9 MUD, 12 SIB, 3 Haplo) and 3 autologous SCT. 21 pts. received reduced intensity conditioning (including 8Gy TBI, n=11) regimens. Among all pts., relapse was the main cause of treatment failure (n=23; 17 BM, 2 CNS, 3 other sites, 1 na), 11 pts. died in CR (6 after HSCT), 34 are in ongoing CR. Based on Kaplan Meier analysis, EFS (events being resistant disease, relapse or death) at 12 months was 74%, with median follow-up of 39 (24-66) months for surviving pts., EFS and OS at 4 years was 42%, and 47%, respectively. By landmark analyses using median time to HSCT as cutoff, cumulative incidence of relapse in transplanted vs. non-transplanted pts. was 32% and 47%, OS at 4 years was 61% and 39%, median OS was not reached versus 3.6 years, respectively (p=ns). The proportion of pts. with a BCR-ABL1/ABL1 ratio ≤0.1% increased from 41% after induction to 86% after consolidation 2; that of pts. with undetectable or non-quantifiable BCR-ABL1 transcripts (sensitivity ≥10-4) increased from 14% to 58%. Conclusions. Nilotinib combined with low-intensity chemotherapy is well tolerated and highly effective in elderly pts. with Ph-positive ALL. OS and EFS compare favorably with previous similar studies testing imatinib or dasatinib. With 32% of pts. undergoing allogeneic HSCT and 61% survival at 4 years, transplantation is a viable option in this elderly cohort of pts.. Disclosures Ottmann: Celgene: Consultancy, Research Funding; Novartis: Consultancy; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Fusion Pharma: Consultancy, Research Funding. Pfeifer:Novartis: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sanhes:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goekbuget:Pfizer: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Celgene: Consultancy; Kite / Gilead: Consultancy; Amgen: Consultancy, Other: Travel support, Research Funding. Dombret:Jazz Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Shire-Baxalta: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Otsuka: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114552

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7

In: The Hematology Journal, Springer Science and Business Media LLC, Vol. 5, No. 2 ( 2004), p. 123-129

Type of Medium: Online Resource

ISSN: 1466-4860 , 1476-5632

URL: Article

DOI: 10.1038/sj.thj.6200353

Language: Unknown

Publisher: Springer Science and Business Media LLC

Publication Date: 2004

In: Cancer, Wiley, Vol. 123, No. 10 ( 2017-05-15), p. 1791-1799

Abstract: Pioglitazone is a peroxisome proliferator‐activated receptor gamma agonist that is able to target quiescent chronic myeloid leukemia stem cells. The combination of imatinib and pioglitazone was well tolerated in vivo and induced a cumulative incidence of conversion to molecular response 4.5 (MR4.5) of 56% by 12 months in 24 CML patients who had a major molecular response under imatinib alone.

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v123.10

DOI: 10.1002/cncr.30490

Language: English

Publisher: Wiley

Publication Date: 2017

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detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5908-5908

Abstract: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) indicated in the treatment of CML-chronic phase (CP), accelerated phase (AP) and blast phase (BP) as well as in patients with the gatekeeper T315I mutation. TOPASE is the real life observatory initiated in France with the participation of 40 CML centers. We report here the interim results of the first 46 patients included in the study as of July 2019, which represents one of the largest real-life Ponatinib study to date in CML. Methods and Aims: CML Patients (Pts) 〉 18 years old, with any stage of disease treated with Ponatinib for a period of less than 6 months or prospectively, were included in the study since February 2018 (ambispective study). The principal aims were the evaluation of efficacy (haematological, cytogenetic and molecular responses), overall survival as well as the safety profile of the use of Ponatinib. After a period of 2 years of inclusion, 2 years of follow-up will be performed until 2022. The study will include 150 patients. Results: 48% of pts were female and 52% males and the median age was 57 +/-18 years. 87% of pts were in CP, 8.7% in AP and 4.3% in BP. The Sokal score was high (34.8% of Pts) intermediate (19.6% pts ) and low (28.3 % pts), not available in 17.4 %. The initiating dose was 15mg in 19 pts, 30mg in 16 pts and 45 mg in 11 pts. All patients with AP/BP except one, were treated with 45 mg/d. Previous therapies were 2 lines (44.4% of pts), 3 lines (26.7% pts), 1 line (17.8% of pts), 4 lines (6.7% of pts), and 5 lines (2.2% of pts) of TKI. The majority of pts had previously Dasatinib (77%) and Imatinib (70%) whereas 43% received Nilotinib and 31% Bosutinib. The last TKI administered prior to inclusion was Dasatinib (40.9% of pts) , Bosutinib (25% of pts) Nilotinib (18.2% of pts) , Imatinib (11.4% of pts) , Ponatinib (2.3% of pts) and ABL001 (2.3% of pts). There was no significant dose-initiation difference with regard to the previous TKI used. The main reason for the initiation of Ponatinib was failure and poor response to previous therapies (63% of pts) followed by intolerance (28.3% of pts). An ABL kinase mutation was detected in 11 patients during their TKI therapy. In 4 pts, the mutation was a T315I and in these pts the last TKI therapy was Nilotinib (n=2), Dasatinib ( n= 1) and Bosutinib ( n= 1). In 7 other patients, previous mutations detected were mostly in p-loop, with previous therapies including Dasatinib, Nilotinib, Imatinib and Bosutinib. One patient previously treated with Dasatinib, Nilotinib and Ponatinib (last therapy) had a F317L mutation, and two pts treated previously with 2 lines (Imatinib, Dasatinib) and 3 lines (Imatinib, Dasatinib, Nilotinib) had E255V/C1135 and F359C / E450K mutations, respectively. At the time of inclusion, the cardiovascular (CV) history of pts (n=46) included high blood pressure (HBP) (35% of pts) or other CV history (26.9%) including peripheral vascular disorders and ischemic heart disease. In the majority of pts with HBP, the initiating dose of Ponatinib was 15 mg/d ( 41%). Other significant medical disorders included diabetes ( 21.7% of pts ) and dyslipidemia ( 8.7% of pts). Results of the efficacy were evaluated at +3 Months (M3) and at +6 months (M6). M3 analyses were available on 18 pts (Figure 1) and M3+M6 analyses on 14 pts. At the entry of the study, the status of the 18 evaluable pts at M3 was as follows: no CHR (n=8), CHR (n=2), no CCyR ( n= 1) CCyR (n= 4), MMR (n=2), MR5 (n=1). At M3, CHR was obtained in 6/8 pts and 4 out of 6 attaining in the same time MMR and 1/6 reaching MR 4.5. For the remaining 10 pts, MMR was obtained in 5/10, and deep molecular responses in 4/10. At M6, out of 14 pts available for molecular analyses, 6 were in MMR, and 3 were in deep molecular responses. 3 pts had no response to Ponatinib. Analysis of responses in individual pts showed that in 8 pts unresponsive to previous therapies 2 had MMR and 1 MR 4. In 10 pts in CHR or absence of CyR, deep molecular responses were obtained in 5/10 pts. Overall, global improvement of responses was obtained in 55.6% at M3 and 60% in M6. At the time of the interim analysis no significant AE were noted for the 46 pts available for analysis. Conclusion: Ponatinib in real life situation is a highly efficient therapy in TKI-resistant and intolerant CML pts. Overall improvement was obtained in 60% of pts with early molecular responses, despite 2 or more previous TKI therapies in 70% of pts. The updated molecular results will be presented concerning M3, M6 and M9 timepoints. Funding : Incyte Biosciences, France Figure 1 Disclosures Guerci: INCYTE: Consultancy, Honoraria. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Huguet:Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Incyte Biosciences: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Berger:Incyte: Consultancy, Honoraria. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Turhan:novartis: Honoraria, Research Funding; Incyte: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-122769

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2553-2553

Abstract: Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19] , p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146412

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3080-3080

Abstract: Abstract 3080 Poster Board III-17 Introduction The combination of imatinib with high-dose chemotherapy has been shown as very promising in patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by several groups. Reported studies all demonstrated a higher response rate and an improved outcome as compared to the pre-imatinib era, but generally with a short follow-up. This was also observed in our GRAAPH-2003 study with complete remission (CR) rate, 18-month disease-free survival (DFS), and 18-month overall survival (OS) of 96%, 51%, and 65%, respectively (de Labarthe et al. Blood 2007). We report here the long-term results of this study with a longer median follow-up of 46 months. Patients & Methods From 2004 to 2005, 45 patients with newly-diagnosed Ph+ ALL (median age, 45 years; range, 16-59 years; 25 males and 20 female) were included in the GRAAPH-2003 study. Briefly, imatinib was started with HAM consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders. Imatinib was administered until allogeneic (if a matched familial donor or an unrelated donor matched at 9 or 10 of 10 HLA antigens) or autologous (if no donor and a good molecular response) stem cell transplantation (SCT). Results were compared with the results of the previous pre-imatinib LALA-94 trial (Dombret et al. Blood 2002). Results When compared to the former LALA-94 study, 4-year OS and DFS were estimated at 52% (36-66) versus 20% (14-26) (p=0.0001) and 43% (27-58) versus 20% (14-28) (p=0.002) in the GRAAPH versus LALA cohorts, respectively. In the GRAAPH-2003, all the 22 CR patients with a donor may receive allogeneic SCT in first CR. In addition, 10 CR patients without a donor but low post-HAM BCR-ABL level received autologous SCT. No significant differences were observed between the donor and the no-donor groups in terms of OS (55% versus 54% at 4 years; p=0.80) and DFS (47% versus 39% at 4 years; p=0.40). This result was partly explained by the good outcome observed in patients who received autologous SCT. The 4-year OS in the allogeneic SCT, autologous SCT, and no SCT groups were 55%, 80%, and 25%, respectively (auto versus allo, p=0.16; auto versus no SCT, p=0.008; allo versus no SCT, p=0.05). The 4-year DFS in the allogeneic SCT, autologous SCT, and no SCT groups were 47%, 50%, and 25%, respectively (auto versus allo, p=0.91; auto versus no SCT, p=0.27; allo versus no SCT, p=0.17). Overall, 4-year cumulative incidences of relapse and death in CR were estimated at 24% (14-40) and 32% (20-49), respectively, underlying the toxicity of the whole GRAAPH-2003 strategy. Notably, 7 of the 22 allografted patients died in CR, as compared to only 1 of the 10 autografted patients. Conclusion We show here that the beneficial impact of the combination of imatinib with chemotherapy is not transient and is preserved in the long term. Taking into account the good outcome of patients receiving autologous SCT and the toxicity of allogeneic SCT, the place and timing of SCT, as well as the optimal chemotherapy to be delivered with imatinib prior to SCT, must be carefully re-evaluated in further prospective trials. Disclosures Dombret: cejgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.3080.3080

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1876-1876

Abstract: Introduction: More than half of adults with ALL suffer a relapse. It is generally accepted that the only curative approach at this stage is stem cell transplantation (SCT). In the LALA-94 trial, we analyzed the outcome in patients (pts) undergoing a first relapse, and evaluated the possibility to undergo SCT. Methods: Of 771 ALL pts (15–55 years (y)) who entered the trial and achieved complete remission (CR), 421 experienced a first relapse between 1994 and 2004. Except for 48 pts who died early before any chemotherapy, all other pts were given re-induction therapy with various salvage chemotherapy regimens (355 pts), autologous SCT (3 pts) with cells harvested in first CR, donor lymphocyte infusions (DLI) (1 pt) or allogeneic (allo) SCT (13 pts) from a geno-identical (7 pts) or a pheno-identical (6 pts) donor. After CR achievement with chemotherapy, pts with an HLA-identical sibling or unrelated donor were systematically assigned to allo SCT (61 pts: 33 from a related-identical donor, 27 from MUD, and one from cord blood). When possible, allo SCT was also proposed to pts refractory to re-induction chemotherapy (24 pts: 14 from a related-identical donor, 7 from MUD, and 3 from cord blood). Results: Overall, 187/421 pts (44%) achieved CR. CR proportion according to risk-groups defined in first line therapy were: 52% for standard-risk ALL, 37% for high-risk ALL, 40% for Ph+ ALL, and 36% for CNS+ ALL. There were no significant differences in CR proportion according to the first CR duration. With a median follow-up of 4.3 y, the median overall survival (OS) was 6.3 months (m). Median disease free survival (DFS) was 5.2 m with 5-y DFS at 12%. The estimated 5-y DFS rates were 11%, and 14% for T- and (Ph neg) B-lineage ALL, respectively. SCT (p 〈 0.0001), first CR duration (p=0.03), and platelets at relapse (p=0.02) were predictors of survival in multivariate analysis. 111/421 pts (26%) had a sibling donor identified during first line therapy and available at relapse. 9 more pts had a sibling donor identified at the time of relapse. Overall allo SCT from a sibling donor could be performed in 54 pts (45% of pts with a sibling donor), and 3 pts received DLI. 40 SCT could be performed from a match unrelated donor (MUD) and 4 from cord blood. Our results showed a significantly higher survival rate at 3 y after SCT in second CR as compared to that of SCT at time of relapse (p = 0.02) or to that of SCT with active disease after failure of reinduction chemotherapy (p = 0.005). When comparing allo SCT from MUD and allo SCT from related-identical donor, survival tended to be better with MUD (3-y OS: 31% vs 21%), in relationship with a lower relapse incidence (RI) (3-y RI: 41% vs 64%) while treatment related mortality (TRM) was quiet similar (TRM at 100 days: 19% vs 35%, and 1-y TRM: 37% vs 46%). Conclusions: Our results showed a second CR in less than 50% of pts and difficulties to organize allo SCT in second CR with however a definitive advantage for pts undergoing SCT when compared to chemotherapy alone. This questions about the opportunity to perform allo SCT, when possible, systematically earlier in the evolution of the disease.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.1876.1876

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7