Kooperativer Bibliotheksverbund

In: The Lancet Haematology, Elsevier BV, Vol. 2, No. 3 ( 2015-03), p. e108-e117

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(15)00020-4

Language: English

Publisher: Elsevier BV

Publication Date: 2015

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 8 ( 2019-04-15), p. 2483-2493

Abstract: Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3+) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1+ and TLX3+ T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes. Experimental Design: We compared TLX1+ and TLX3+ adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase (ASNS) and in vitro l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples. Results: We show that TLX1+ patients expressed low levels of ASNS when compared with TLX3+ and TLX-negative patients, due to epigenetic silencing of ASNS by both DNA methylation and a decrease of active histone marks. Promoter methylation of the ASNS gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally, ASNS promoter methylation was an independent prognostic factor for both event-free survival [HR, 0.42; 95% confidence interval (CI), 0.24–0.71; P = 0.001] and overall survival (HR, 0.40; 95% CI, 0.23–0.70; P = 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas (P = 0.012). Conclusions: We conclude that ASNS methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-18-1844

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2019

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

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

detail.hit.zdb_id: 2186022-1

detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: International Journal of Molecular Sciences, MDPI AG, Vol. 19, No. 8 ( 2018-08-20), p. 2464-

Abstract: Dormancy is an adaptive trait that blocks seed germination until the environmental conditions become favorable for subsequent vegetative plant growth. Seed dormancy is defined as the inability to germinate in favorable conditions. Dormancy is alleviated during after-ripening, a dry storage period, during which dormant (D) seeds unable to germinate become non-dormant (ND), able to germinate in a wide range of environmental conditions. The treatment of dormant seeds with ethylene (D/ET) promotes seed germination, and abscisic acid (ABA) treatment reduces non-dormant (ND/ABA) seed germination in sunflowers (Helianthus annuus). Metabolomic and transcriptomic studies have been performed during imbibition to compare germinating seeds (ND and D/ET) and low-germinating seeds (D and ND/ABA). A PCA analysis of the metabolites content showed that imbibition did not trigger a significant change during the first hours (3 and 15 h). The metabolic changes associated with germination capacity occurred at 24 h and were related to hexoses, as their content was higher in ND and D/ET and was reduced by ABA treatment. At the transcriptional level, a large number of genes were altered oppositely in germinating, compared to the low-germinating seeds. The metabolomic and transcriptomic results were integrated in the interpretation of the processes involved in germination. Our results show that ethylene treatment triggers molecular changes comparable to that of after-ripening treatment, concerning sugar metabolism and ABA signaling inhibition.

Type of Medium: Online Resource

ISSN: 1422-0067

URL: Article

DOI: 10.3390/ijms19082464

Language: English

Publisher: MDPI AG

Publication Date: 2018

detail.hit.zdb_id: 2019364-6

SSG: 12

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

detail.hit.zdb_id: 1468538-3

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

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer Medicine, Wiley, Vol. 8, No. 11 ( 2019-09), p. 5173-5182

Abstract: To assess the incidence of BCR‐ABL kinase domain (KD) mutation detection and its prognostic significance in chronic phase chronic myeloid leukemia (CP‐CML) patients treated with tyrosine kinase inhibitors (TKIs). Patients and Methods We analyzed characteristics and outcome of 253 CP‐CML patients who had at least one mutation analysis performed using direct sequencing. Of them, 187 patients were early CP (ECP) and 66 were late CP late chronic phase (LCP) and 88% were treated with Imatinib as first‐line TKI. Results Overall, 80 (32%) patients harbored BCR‐ABL KD mutations. A BCR‐ABL KD mutation was identified in 57% of patients, who progressed to accelerated or blastic phases (AP‐BP), and 47%, 29%, 35%, 16% and 26% in patients in CP‐CML at the time of mutation analysis who lost a complete hematologic response, failed to achieve or loss of a prior complete cytogenetic and major molecular response, respectively. Overall survival and cumulative incidence of CML‐related death were significantly correlated with the disease phase whatever the absence or presence of a mutation was and for the latter the mutation subgroup (T315I vs P‐loop vs non‐T315I non‐P‐loop) ( P 〈 .001). Considering patients who were in CP at the time of mutation analysis, LCP mutated patients had a significantly worse outcome than ECP‐mutated patients despite a lower incidence of T315I and P‐loop mutations ( P 〈 .001). With a median follow‐up from mutation analysis to last follow‐up of 5 years, T315I and P‐loop mutations were not associated with a worse outcome in ECP patients ( P  = .817). Conclusion Our results suggest that early mutation detection together with accessibility to 2nd and 3rd generation TKIs have reversed the worst outcome associated with BCR‐ABL KD mutations whatever the mutation subgroup in CP‐CML patients.

Type of Medium: Online Resource

ISSN: 2045-7634 , 2045-7634

URL: Issue

URL: Article

DOI: 10.1002/cam4.v8.11

DOI: 10.1002/cam4.2410

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 2659751-2

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4018-4018

Abstract: Purpose: Hyper-CVAD developed by the MD Anderson group a few years ago, is one of the standard salvage regimen used for younger relapsed/refractory ALL patients. Recently, targeted therapies using monoclonal antibodies directed against such surface antigens as CD19, CD20 or CD22 have allowed to obtain complete remission (CR) in B ALL expressing these markers. We hypothesized that combining Hyper-CVAD and an anti-CD22 monoclonal antibody could improve the response of such patients. Materials and Methods: This study evaluated the Cheprall salvage regimen, where epratuzumab, a humanized therapeutic monoclonal antibody against CD22 with mainly ADCC property, was associated to Hyper-CVAD, in younger patients (18-59 years old) with relapsed/refractory CD22+ ( 〉 30% of expression) B-ALL. Cheprall consisted of epratuzumab 360 mg/m²/d iv on days 1, 8, 15 and 22, cyclophosphamide 300 mg/m²/12h iv on days 1 to 3, vincristine 2 mg iv on days +4 and +11, doxorubicin 50 mg/m² iv on day +4 and dexamethasone 40 mg po on days 1 to 4 and 11 to 14. The main objective of the study was the overall response rate (CR + CR with incomplete platelets recovery ( 〈 100 000/mm3, CRp) + partial response (PR, 〉 =50% of bone marrow (BM) blasts decrease or CR with persistent extramedulladory disease) evaluated between 4 and 6 weeks from day+1. Secondary objectives were overall (OS) and leukemia free (LFS) survivals and minimal residual disease (MRD) evaluated by flow cytometry. Results: Between January 2011 and April 2016, 31 patients from 11 French centres were enrolled in the study. A combination of epratuzumab + vincristine and dexamethasone (EVD) only was given to one patient subsequently excluded from the analysis. Among the 30 patients ultimately considered for analyses, 19 were males and the median age was 35 years (range: 21-59). The median time between diagnosis and Cheprall was 14.5 months (range: 4-130) and 13 patients had been allotransplanted. Disease status at time of Cheprall was as follows: primary refractory n=3; first relapse non treated n=13; refractory first relapse n=6, second relapse non treated n=7 and fourth relapse n=1. Median percentage of white blood cells and BM blasts were 4525/mm3(range: 90-86790) and 60% (range: 15-100), respectively. The median CD22 expression of BM blasts was 100% (range: 36-100). Four patients had extramedullary disease: breast n=2, parotid n=1, nervous central system n=1 (deviation). Cheprall was overall well tolerated including mostly pancytopenia as grade ¾ toxicities. Three patients died during aplasia (septis n=1; cerebral haemorrhage n=1, fusariosis n=1) and were not evaluable for response. The overall response rate was 50% (n=15) including 9 CR (30%), 1 CRp (3%) and 5 PR (17%). The number of CR/CRp was higher for patients in first non-treated relapse (54% vs 18%) with an age below 36 years (50% vs 14%), with 〈 =50% of BM blasts (57% vs 26%) and with a delay between diagnosis and Cheprall 〉 18 months (54% vs 17%). Four out of 9 evaluated CR/CRp patients (45%) were documented with negative MRD. All patients in CR/CRp and 1 patient in PR received a consolidation consisting of a second cycle of Cheprall n=5, EVD n=5 or blinatumomab n=1. At the time of analysis (July 2016), all patients have died (during aplasia n=3, progression n=23, multiple organ failure n=1), except three responders still in CR, but yet recently enrolled (2015 n=1, 2016 n=2). Six patients received allogeneic transplant after Cheprall: 4 in CR2, 1 as salvage treatment and 1 in CR3. The last patient included and who achieved CR2 should be allografted in August 2016. Median OS was 3 months (range: 0.2-34.8). Median LFS for those achieving CR/CRp was 4.5 months (range: 1-12). Conclusion: Hyper-CVAD + epratuzumab allowed to obtain 50% of response in this cohort of patients at high risk of failure with refractory/relapsed younger CD22+ B-ALL. Disease improvement was however short-lived, which could be explained either by an insufficient disease load decrease and/or by escape of the blast cells to epratuzumab. This partial efficacy in a population of poor prognosis may suggest that epratuzumab should be tested within first-line chemotherapies as it may participate to decrease MRD level, especially before transplantation. The trial was registered at http://clinicaltrials.gov/ct no.NCT01219816. This study was supported by a grant from the French National Cancer Institute (PHRC 2010). Disclosures Huguet: Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Thomas:Pfizer: Consultancy. Goldenberg:Immunomedics: Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Wegener:Immunomedics: Employment, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4018.4018

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 494-494

Abstract: The combination of 2GTKI+pegylated IFN-α (Peg-IFN) is an attractive approach for first-line treatment of CP CML, inducing high rates of deep molecular responses in phase II trials. Thus, 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). Newly diagnosed CP CML pts ≤65 y, without prior history of arterial occlusion were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone for 30 days (M-1→M0) 30 μg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 wks, upgraded to 45 μg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone for 4 more years unless pts enter treatment-free remission (TFR). The primary endpoint is the rate of MR4.5 by 1 y. As a secondary endpoint, pts reaching MR4.5 ≥2 y are allowed to stop NIL and enter a TFR phase in both arms. The trigger for treatment resumption is loss of MMR. All molecular assessments are centralised, quantifications are expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Two hundred pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. Median follow-up is 43.8 (34.3-55.9) Mo. Results are analysed in intention-to-treat. Sokal and EUTOS LTS scores were H in 25% and 2.5%, Int. in 33% and 16.5% and L in 42% and 81% pts respectively equally balanced. Median age is 46 (18-66) y, 18 pts (9%) had ACAs, all pts have a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (in B) and 88% of pts in A and 90.4% of pts in B at M1. CCyR rates at M3 were 63% vs 75% in A and B (p=ns), and BCR-ABL1 ≤1% at M6 were 87% in A vs 93% in B (p=ns). By M12, the rates of MMR were 68.1% vs 70.1% (p=0.44), MR4 were 34% vs 47.5% (p=0.041), MR4.5 were 15.9% vs 21.5% (p=0.049), MR5 11.7% vs 23.71% (p=0.023), in A vs B respectively. By M36 the rates of MMR were 83% vs 86.6% (p=0.31), MR4 were 70.2% vs 71.13% (p=0.50), MR4.5 were 37.2% vs 49.5% (p=0.05), MR5 33% vs 42.3% (p=0.12), in A vs B respectively The overall cumulative incidence of MR4.5 is superior in B (54.6 [43.7-65.5] %) vs A (44 [31.5-54]%) close to significance (unilateral Fisher test, p=0.05, see Figure). Seven patients were mutated by Sanger in A (5 Y253, 1 E255K, 1 T315I) vs 2 in B (2 T315I). One pt (A) progressed toward AP and then myeloid BC with a Y253H mutation, is still alive in CMR on Ponatinib. Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator decision 5), 1 pt died from cervix cancer (A). Median overall doses of NIL delivered by M36 were 600 mg/d in both arms (p=ns). The median overall dose of Peg-IFN delivered in B by M24 was 37.5 mg/wk. The overall rate of grade 3-4 hematologic toxicities was 22%; with 2% and 7% thrombocytopenia, 4% and 6% neutropenia, and 1% and 1% pancytopenia in A vs B respectively. Major grade 3-4 non-hematologic toxicities consisted in 9% of cardiac disorders in A (2 coronaropathies, 1 myocardial infarction, 2 thoracic pains, 2 atrial fibrillation, 1 bradycardia, 1 palpitations, 1 pericarditis) vs 8% in B (2 coronaropathies, 1 myocardial infarction, 3 atrial fibrillation, 1 palpitations, 1 pericarditis), 4% vascular disorders in A (1 thrombophlebitis + PE, 1 transient ischemic attack, 1 PAOD, 1 carotid stenosis) vs 3% in B (1 thrombophlebitis, 1 PAOD, 1 transient ischemic attack). Three % of gastro-intestinal disorders were observed in A (2 pancreatitis, 1 anal fissure) vs 6% in B (2 pancreatitis, 1 anal fissure, 1 abdominal pain, 2 cholecystectomies); 5% auto-immune disorders in B (1 recurrent pericarditis, 2 hemolytic anemia, 1 ITP, 1 thyroiditis); 5 and 8 pregnancies (2 pts + 3 partner Arm 1, 3 pts + 5 partner Arm B), despite recommended contraceptive methods. Secondary tumours were diagnosed in 4% (1 breast, 1 cervix, 1 thyroid, 1 neuroendocrine) in A vs 2% of pts (1 neuroendocrine and 1 testis) in B. Of note 8% psychiatric episodes were reported in B pts (2 unsuccessful suicide attempts), vs 2% in A. We observed 9% lipase elevations in A, 6% in B, 2% cholestatic episodes in A, 6% in B; 3% of transaminase elevations in A vs 2% in B. Infections were detected in 3% A vs 7% in B. The combination of NIL + Peg-IFN seems to provide somewhat higher MR4.5 rates by M36 in newly diagnosed CP CML pts without inducing significant higher toxicities than NIL alone. Whether this will translate in higher TFR rates is under evaluation. Final updated results at M36 will be presented Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Novartis: Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Huguet:Servier: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Charbonnier:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Legros:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria. Coiteux:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy. Roy:Incyte Biosciences: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Ame:Incyte Biosciences: Honoraria, Speakers Bureau. Rea:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria; BMS: Honoraria. Dulucq:Novartis: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. OffLabel Disclosure: Pegylated Interferon alpha 2 a is not licensed in this setting

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123674

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7