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  • 1
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    Impact of ATRA Duration during the Induction Treatment of Newly Diagnosed APL
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 139-139
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 139-139
    Abstract: Background: ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL. ATRA has also demonstrated a role during maintenance treatment in randomized studies (Fenaux, Blood 99; Talmann, NEJM 1997), and may even be useful during consolidation courses (Sanz, Blood, 2008, although this was not a randomized study). During induction treatment, the optimal duration of ATRA treatment, however, is unknown. We tried to assess this point using long-term results of APL 93 and APL 2000 trials, conducted by the European APL group in newly diagnosed APL between 1993 and 2004. Methods: APL 93 and 2000 trials combined ATRA plus 3 courses of daunorubicin (DNR) based CT and included a total of 902 pts with different randomizations (for date of introduction of CT, use or not of AraC and of maintenance treatment). Only treatment arms that proved “optimal” (ie with early addition of the first course of CT to ATRA, AraC in combination to DNR for the 3 CT courses, and combined maintenance with intermittent ATRA and low dose continuous CT) (Fenaux, Leukemia 2000;Ades JCO 2006) and adult pts who had achieved CR in those arms, ie 414 pts, were considered for this analysis of the influence of duration of ATRA during induction treatment on the cumulative incidence of relapse (CIR) and survival. Per protocol, ATRA (45 mg/m2/d, rounded to a daily dose of 8 pills of 10 mg per day, ie 80 mg/day in most pts) was to be administered “until CR”, and to be transiently discontinued only in case of severe ATRA syndrome. No dose reduction was allowed except in children, who were therefore excluded from this analysis. Results: In the 414 pts, who Included 263 (64%) pts with WBC & lt; 10G/L and 151(36%) pts with WBC & gt;10G/L, the median cumulative dose of ATRA administered during Induction treatment was 2160 mg (corresponding to 27 days at 80 mg/d) Early ATRA Interruptions, Ie before recovery from aplasia and patient discharge, were made almost exclusively for ATRA syndrome or unexplained fever, and were followed or not by restart of the drug. Final discontinuation of ATRA for induction treatment was made a median of 27 days after onset of ATRA treatment. Although both trials stated that ATRA should be continued “until CR”, ATRA discontinuation was more often made at the end of the period of aplasia and patient discharge, than at the time of documented CR on bone marrow examination, especially as marrow abnormal promyelocytes are known to disappear slowly in APL. No difference in 5 y CIR or survival were found in pts who had received more or less than 2160 mg of ATRA during induction in the whole population and in pts with baseline WBC less or greater than 10 G/L. 89/414 (21%) pts had received less than 1500 mg of ATRA during Induction (corresponding to less than 19 days at 80 mg/day), their 5 y CIR and survival were similar to those of pts who had received more than 1500 mg of ATRA during induction in the whole population, and in pts with baseline WBC & gt; 10 G/L. However, in pts with baseline WBC & lt;10G/L (263 pts), the 5 year CIR, and survival were 31.3% and 12.5% (p = 0.04) and 81.1% and 95.3% (p = 0.022), in patients who had received less and more than 1500 mg of ATRA during induction treatment, respectively. Differences persisted after adjustment on other prognostic factors of relapse Identified in our previous studies, including gender, baseline platelet count, circulating blasts and fibrinogen level and on the clinical trial (APL 93 vs APL 2000). Conclusion: Although ATRA duration for induction treatment was not randomized in APL 93 and 2000 trials, our results suggest that, in newly diagnosed APL pts with WBC & lt; 10 G/L, short duration of ATRA during induction treatment may be associated with a higher risk of relapse. This, along with Spanish PETHEMA results supporting a possible role for ATRA during consolidation courses, suggests that sufficiently prolonged exposure to ATRA during the first months of treatment (and not only during maintenance) may be important for disease cure in APL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.139.139
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 2
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    Arsenic Trioxide (ATO) In the Consolidation Treatment of Newly Diagnosed APL - First Interim Analysis of a Randomized Trial (APL 2006) by the French Belgian Swiss APL Group
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 505-505
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 505-505
    Abstract: Abstract 505 Background: ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL, but this treatment is myelosuppressive and may be associated with long term cardiac toxicity. The use of ATO may allow reduction of the amount of CT (and in particular avoid ara C), and further diminish the relapse risk, especially when used in consolidation treatment (US intergroup study, Powell, ASCO 2008). In a randomized trial, we used ATO for consolidation treatment instead of ara C in standard risk APL (baseline WBC 〈 10G/L), and in addition to AraC in high risk patients (baseline WBC 〉 10G/L). ATRA, suggested to reduce the relapse risk when used during consolidation (Sanz, Blood 2008, 112: 3130-4) was also tested in standard risk pts. Methods: In APL 2006 trial (started in Nov, 2006) newly diagnosed APL patients (pts) 〈 70 years with WBC 〈 10 G/L were randomized between: group A1( standard group) (induction: ATRA 45mg/m2/d until CR with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3; first consolidation with the same CT course, second consolidation with Ida 12 mg/m2/dx3 and AraC 1g/m2/12h x4d; maintenance during two years: intermittent ATRA 15d/3 months and continuous 6 MP + MTX,); Group A2: same treatment as group A1, but AraC replaced by ATO 0.15 mg/Kg/D D1 to 25 days of both consolidation courses; Group A3: same treatment as group A1, but AraC replaced by ATRA 45 mg/m2 d1 to 15 of both consolidation courses. Pts aged 〈 70 with WBC 〉 10G/L (Group C) were randomized between: group C1 (standard group): same treatment as Group A1; group C2: same as C1, but with addition of ATO 0.15 mg/Kg/d d1 to 25 of both consolidation courses, at d1. Pts with WBC 〉 10 G/L all received intrathecal CT for CNS prophylaxis. This first interim analysis was made at the reference date of 1 Jan 2010, in 186 pts aged 〈 70 years included in 78 centers before 2009 (141 pts in group A (45/45/51 pts in A1/A2/A3 arms), 45 pts in group C (24/21 pts in C1/21 arms)). Results: In standard risk patients (group A) 140 (99.3 %) patients achieved CR, and 1 (2%) had early death. After a median follow up of 22.1 months, 1, 0, and 1 pts had relapsed in the A1, A2 and A3 consolidation groups, resp. (18 months cumulative incidence of relapse- CIR-of 0%, 0% and 2%). 2, 2, and 0 pts had died in CR in the A1, A2 and A3 consolidation groups, resp. The median duration of neutropenia and thrombocytopenia during consolidation courses was 43.5 and 44 days, 40 and 35 days, 20 and 25 days after consolidation cycles in groups A1 (AraC), A2 (ATO) and A3 (ATRA), resp (p 〈 0.01). The median overall duration of hospitalization was 51, 59 and 26 days in A1,A2 and A3 groups, respectively. In high risk pts (group C) 45 (100 %) patients achieved CR. After a median follow up of 23.7 months, 1 and 1 pt had relapsed in the C1 and C2 consolidation groups, resp (18 months CIR of 2% and 2%). One and 3 had died in CR in the C1 and C2 consolidation groups, resp. Median duration of neutropenia and thrombocytopenia was 45.5 and 43.5 days, 51.5 and 48 days, after consolidation cycles in groups C1(AraC) and C2 (AraC+ATO), resp. The median overall duration of hospitalization was 53.5, and 65 days in C1 and C2 groups, respectively. Conclusion: Results of this first interim analysis show that very high CR rates ( 〉 95%) can be observed in very multicenter trials in APL, by combining ATRA and anthracycline based CT, while the relapse rate with consolidation and maintenance was very low in all treatments arms, including in pts with WBC 〉 10G/L. Nevertheless ATO, when combined to high dose CT during consolidation cycles, increased myelosuppression. An amendment further reducing CT in pts receiving ATO is thus being implemented in the trial. Disclosures: Off Label Use: ATO as 1st line treatment in APL. Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.505.505
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Arsenic Trioxide (ATO) Or ATRA For Consolidation Treatment Of Standard Risk Non Elderly Newly Diagnosed APL– Second Interim Analysis Of a Randomized Trial (APL 2006) By The French Belgian Swiss APL Group
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 495-495
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 495-495
    Abstract: Background ATRA combined to anthracycline-based chemotherapy (CT) remains the classical treatment of newly diagnosed APL, but it is myelosuppressive and may be associated with long-term cardiac toxicity. Both ATO (Powell, Blood 2010) and ATRA (Sanz , Blood 2004) may allow to reduce the amount of CT and further diminish the relapse risk. In a randomized trial (APL 2006 trial), we compared for consolidation treatment ATO, ATRA and Ara C in standard risk APL ( ie with baseline WBC 〈 10G/L). Methods In this trial (started in Nov, 2006) newly diagnosed APL patients (pts) 〈 70 years with WBC 〈 10 G/L were randomized for consolidation between AraC, ATO and ATRA. The AraC group (standard group) received for induction: ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3; first consolidation with the same CT course, second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d ; maintenance during two years with intermittent ATRA 15d/ 3 months and continuous 6 MP + MTX,). The ATO and ATRA groups received the same treatment as the AraC group , but AraC was replaced respectively by ATO 0.15 mg/Kg/d d1 to 25 and ATRA 45 mg/m2/d d1 to 15 for both consolidation courses. We present here results of the second interim analysis, made at the reference date of 1st Jan 2012, in 349 pts aged 〈 70 years included in 78 centers before 2012. The primary endpoint was event free survival (EFS) at 2 years from CR achievement. Relapse, survival, side effects of the treatment and duration of hospitalization were secondary endpoints. Results Pre-treatment characteristics were well balanced between the 3 consolidation groups. 347 pts (99.4 %) achieved CR, and 2 (0.5%) had early death. Overall, 3, 0, and 4 pts had relapsed and 5, 2, and 2 pts had died in CR in the AraC, ATO and ATRA consolidation groups, respectively. Two year EFS was 95%, 97.4% and 96.8% (p=NS) and 2 year OS was 96.6%, 97.4% and 99% (p=NS), in the AraC, ATO and ATRA consolidation groups, respectively. Median time to ANC 〉 1 G/L and platelets 〉 50G/L after the first consolidation course was 24 and 25 days, 24 and 23 days, 17 and 20 days in the AraC, ATO and ATRA group, respectively (p 〈 0.01). Similarly, time to ANC 〉 1 G/L and platelets 〉 50G/L after the second consolidation course was 23 and 27 days, 19 and 18 days, 13 and 19 days in the AraC, ATO and ATRA group (p 〈 0.01). The overall duration of hospitalization was 60.9, 63.1 and 33 days in in the AraC, ATO and ATRA groups, respectively (p 〈 0.01). Conclusion Very high CR rates (close to 98-99%) are now obtained in standard risk APL on a very large multicenter basis using classical ATRA and anthracycline based CT combinations, with very few relapses. ATO or ATRA can replace AraC during consolidation cycles without increasing the relapse risk, and can possibly reduce the rate of deaths in CR (2 and 2 patients versus 5 patients, although the difference was NS). However Ida and ATO, when used concomitantly for consolidation cycles, proved as myelosuppressive as Ida-AraC cycles, while myelosuppression was reduced with Ida-ATRA consolidation courses. Disclosures: Off Label Use: ATO in the treatment of 1st Line APL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.495.495
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    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    A Phase I Study of the Anti-Natural Killer Inhibitory Receptor (KIR) Monoclonal Antibody (1-7F9, IPH2101) in Elderly Patients with Acute Myeloid Leukemia (AML): Clinical and Immunological Effects of a Single Dose Followed by Repeated Dosing.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 632-632
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 632-632
    Abstract: Abstract 632 Background: Non cytotoxic treatments such as immunotherapy represent promising approaches for the post-remission therapy of elderly patients with AML for which relapse free survival is short. The therapeutic potential of natural Killer (NK) cells has been revealed by the KIR mismatch allogeneic transplant model where the anti-leukemic effect of the graft is due to unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts (Miller et al. 2005; Ruggeri et al. 2002). To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs), the 1-7F9/IPH2101, was generated (Romagne et al., Blood 2009). We present the results of the First in Human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60-80 years with non promyelocytic AML in first CR following induction and 1-6 cycles of consolidation chemotherapy, normal renal and hepatic functions, KIR-expression on NK-cells and who signed informed consent were eligible for Protocol IPH2101-101. Dose escalation (IPH2101: 0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as iv infusion) was studied using a 3+3 scheme. Patients still in CR who had tolerated the single dose administration were eligible for an extension trial (Protocol IPH2101-102) investigating repeated doses of IPH2101 (1/ month x 6 months) using the dose the patient was allocated to in protocol IPH2101-101. Pharmacokinetic (PK) and circulating cytokines (IL-1b, IL-6, IFN-g, MIP-1β and TNF-a) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: 23 patients, median age 71 years (range 61-79) in first CR of AML for a median of 20 weeks have been included in IPH2101-101. 3 patients (13%) had achieved CR after 2 induction courses, 5 patients (22%) had unfavorable cytogenetics, and 5 patients (22%) had high WBC at diagnosis. Planned dose escalation has been completed and no Dose Limiting Toxicity (DLT) has been recorded. 2 patients (in DL 4 and 5) have been replaced (one relapsed before 4 weeks of follow-up; the other had no detectable antibody after injection). Related Adverse Events seen in 14/23 patients (61%) were mild (grade ≤2) and transient. For doses above 0.075 mg/kg, ½ life ranged between 11-28 days. For doses above 0.3mg/kg, full saturation ( 〉 90% KIR occupancy) has been observed for 28 days to up to 6 weeks (at the 3 mg/kg DL). IPH2101 had no effect on the number and distribution of the peripheral lymphocyte subsets or the expression of NK receptors (KIRs, CD94/NKG2A, CD85j, NKp46, NKp30 or NKG2D). NK cell function tested by ex vivo cytotoxicity assay was not impaired after treatment. From dose 1 mg/kg (5/6 patients), IL-1b and IL-6 increased 6h post-dosing (2 to 8 fold increase and 2 to 15 fold increase compare to pre-dose, respectively) and decreased to pre-dose concentrations within 24h. Furthermore increase in TNF-a during the first hour was often correlated with CD69 up-regulation on NK cells. 8 patients received repeated doses of IPH2101 (0.0003 mg/kg: 2 patients, 0.003 mg/kg: 2 patients, 0.015 mg/kg: 1 patient, 1 mg/kg: 3 patients, 3 mg/kg pending) as part of the extension trial. No grade 3-4 related toxicities were observed. 2 patients completed the 6 courses, 5 patients were withdrawn for relapse and 1 patient is still ongoing at 1mg/kg. In accordance with the pre-clinical PK/PD model there is a clear relationship between exposure (Cmax) and KIR occupancy. Moreover the inter-patient variability is low (PK data) to moderate (KIR occupancy data). Median follow-up is 47 weeks. Among the 21 evaluable patients 11 patients are alive, 15 relapsed with 10 death, 6 are still in remission (1 patient in DL1, 2 patients in DL6 and 3 patients in DL7). Conclusions: Anti KIR treatment is safe and well tolerated and MTD has not been reached for doses producing full KIR saturation for 4 weeks, confirming the specificity of the immunological effects. Retreatment for prolonged period of time is feasible and safe. Signs of NK cell activation can be observed for doses above 0.3 mg/kg. IPH2101 deserves further investigation in patients with AML. Disclosures: Vey: INNATE PHARMA: Consultancy. d'Arnoux:INNATE PHARMA: Employment. Romagne:INNATE PHARMA: Employment. Andre:INNATE PHARMA: Employment. Tiollier:INNATE PHARMA: Employment. Squiban:INNATE PHARMA: Employment. Blaise:INNATE PHARMA: Consultancy. Olive:INNATE PHARMA: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.632.632
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 5
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    Treatment of High Risk MDS and AML Post-MDS with Azacytidine (AZA): Preliminary Results of the French ATU Program.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 2664-2664
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 2664-2664
    Abstract: Background : Following FDA approval of AZA for MDS and activation of a phase III trial randomizing AZA to conventional treatment in higher risk MDS, a compassionate program for the use of AZA (ATU nominative) was started in France for MDS with exclusion criteria for this trial. Patients (pts) : IPSS int-2 and high-risk MDS (and some int-1) with contra-indication to the trial (ie therapy related (t-MDS) or already treated by cytoreductive agents or having progressed to AML or patient refusal), received AZA 75 mg/m/d (d 1–7) (SC) every 4 weeks. Results : From Sept 2004 to May 2006, 90 pts from 31 centres were included, of whom 77 had completed at least one course of AZA : M/F: 52/25, median age 71 y [42–88]. WHO at inclusion : 15 RAEB1, 30 RAEB2, 14 AML post-MDS, 7 CMML, 3 RA, 3 RAS, 2 RCMD, 3 unclassified MDS. 22 pts had previously received intensive Anth-AraC, 9 low dose AraC, 16 EPO and 13 other treatments (alkylators, Arsenic, androgens, Thal) and 1 had t-MDS. 32 (42%), 16 (21%) and 29 (37%) pts had fav, int and unfav karyotype, resp. 37 pts (48%) were IPSS high, 26 pts (34%) int-2 and 14 pts (18%) int-1. Pts received a median of 4 cycles [range 1–16] . Response was generally assessed after 4 cycles, unless pts progressed before. Thus, 16 pts were not yet evaluable for response. Of the remaining 61 pts, 10 (16%) achieved CR (IWG criteria), 15 (25%) achieved PR and 13 (21%) achieved HI (Overall response rate OR=62%). 23 pts (38%) were considered failure of whom 4 died before evaluation and 10 of them were considered failure because early evaluation after only 2 cycles showed stable disease only, and AZA was then stopped. OR was 73%, 57%, 67% and 36% for RAEB1, RAEB2, CMML and AML post-MDS resp (p 〈 0.1); 75%, 56% and 59% for fav, int and unfav karyotype, resp (p=NS). 4/6 pts with monosomy 7 responded (1 CR+3 PR), 2/4 pts with + 8 (1 PR+1 HI) and 13/23 pts with complex karyotype (5 CR+6 PR+2 HI). OR was 56%, 77% and 56% for IPSS high, int-2 and int-1 pts, resp (p=NS) and 50%, 76% in pts previously treated or not by cytoreductive agents resp (p 〈 0.05). Median survival from inclusion was 7 months [range 3–17]. AZA induced myelosuppression lead to dose reduction in 17% pts and hospitalization in 13% pts but was not responsible for any death. Other side effects included frequent local reactions (reversible with local NSAID) (32%), grade I-II gastro-intestinal disorders (39%), unexpected cardiac arythmias (3%). Conclusion : AZA, in this population with overall unfavorable features, gave response rates at least similar to those of CALGB studies, that may have been higher if treatment had not been stopped in some of the pts stable after 2 courses. Pts with unfavorable karyotype (− 7, complex) or + 8 had about 50% response rates. Accrual in this program is continuing. Data on response duration will be presented.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2664.2664
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 6
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    A randomised phase II study of azacitidine ( AZA ) alone or with Lenalidomide ( LEN ), Valproic acid ( VPA ) or Idarubicin ( IDA ) in higher‐Risk MDS or low blast AML : GFM 's “pick a winner” trial, with the impact of somatic mutations
    Wiley ; 2022
    In:  British Journal of Haematology Vol. 198, No. 3 ( 2022-08), p. 535-544
    Details
    In: British Journal of Haematology, Wiley, Vol. 198, No. 3 ( 2022-08), p. 535-544
    Abstract: In order to improve the outcome observed with azacitidine (AZA) in higher‐risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA‐PLUS was a phase II trial that, in a “pick a winner” approach, randomly assigned patients with higher‐risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA‐LEN And AZA‐IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy‐related MDS and, in the case of TP53 , PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our “pick a winner” randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.v198.3
    DOI: 10.1111/bjh.18193
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    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 7
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    Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: Results from the GET-LALA group
    Elsevier BV ; 2008
    In:  Leukemia Research Vol. 32, No. 11 ( 2008-11), p. 1741-1750
    Details
    In: Leukemia Research, Elsevier BV, Vol. 32, No. 11 ( 2008-11), p. 1741-1750
    Type of Medium: Online Resource
    ISSN: 0145-2126
    URL: Article
    DOI: 10.1016/j.leukres.2008.04.011
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
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  • 8
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    Therapy Related Myeloid Neoplasm Post PARP Inhibitors: Potential Clonal Selection.
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 14-15
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    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 14-15
    Abstract: Introduction Clonal selection is one of the mechanisms leading to therapy-related myeloid neoplasms (TRMN). A preexisting somatic mutation in hematopoietic stem cell (defined as clonal hematopoiesis [CH]) emerges under pressure of chemotherapy or radiotherapy, leading to TRMN development. Most of these mutations belong to the DNA damage response (DDR) pathway as TP53 or PPM1D mutations and are known to confer a dismal prognosis. Recently authorized for the treatment of ovarian cancers (OC), the poly (ADP-ribose) polymerase inhibitors (PARPi) represent a promising targeted therapy. However, by inducing DNA damage and altering DNA repair process, PARP inhibition could represent a challenge for the genetic stability of the healthy tissues. Thus, we assessed the effect of PARP inhibition on the development of CH and TRMN after PARPi treatment for OC (TRMN-PARPi) in combination with chemotherapies. Methods Firstly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in 13 patients exposed to PARPi without TRMN. Secondly, we retrospectively identified, with the help of the UNIHEM group of Unicancer, 17 patients who experienced TRMN-PARPi. Clinical, biological and survival data were collected and compared to 23 OC patients with TRMN not treated with PARPi (Gustave Roussy institutional database). Lastly, NGS was performed for 3 patients with TRMN-PARPi with sequential sampling. Patient's samples were obtained with informed consent. Results Thirteen OC patients during maintenance treatment with PARPi without TRMN were explored by NGS. Median age at NGS was 64.5 years old (yo) (40.5-75.3). 4/13 (31%) patients harbored BRCA1/2 germline mutation. Time between OC diagnosis and NGS was 4.3 y (1-11.6). The median number of chemotherapy line at PARPi initiation was 2 (1-3). 7 received Olaparib, 5 Niraparib and 1 Rucaparib. The median duration of PARPi treatment before NGS was 4.7 months (1.1-25.1). 12/13 patients experienced hematological toxicities during the PARPi treatment. CH was found in 10/13 (77%) patients (Figure 1a), including mutations of DDR genes in 8/10 (80%). 6/8 (75%) patients had 2 or more gene mutations. Next we identified 17 cases of TRMN occurring during or after PARPi administration for OC (6/17 [35%] t-AML and 11/17 [65%] t-MDS). 12/17 (71%) patients had BRCA germline mutations (7 BRCA1 and 5 BRCA2). All received Olaparib with a median dose of 600mg/d (400-1200). Median duration of Olaparib treatment was 1.7 years (0.2-4.6). TRMN-PARPi were described 1.4 months (0-10.9) after the end of PARPi administration. We compared these patients to a cohort of TRMN post OC not treated by PARPi. Number of therapy lines for OC, time between TRMN and OC diagnosis, median age at TRMN, were, for TRMN-PARPi, 2 (1-8), 5.9 y (0.9-20.8), 64.4 yo (46-74); respectively, compared to 3 (1-8), 4.9 y (1.7-36.9), 59.3 yo (35.7-85.7); (p=ns). TRMN-PARPi cytogenetic was unfavorable for 16/17 (94%) (including 11/17 [65%] complex karyotype) compared to 16/23 (70%) (11/23 [48%] complex karyotype). C Median survival was significantly lower in the TRMN-PARPi group 3.9 months 95%CI [2.0-9.7] and 6.1 months 95%CI [4.1-15.8] respectively, p=0.046, Fig 1b). However, median survival from OC diagnosis was not different between the two groups 6.2 y 95%CI [5.6-NA] for TRMN-PARPi vs 5.6 y 95%CI [5.0-11.6] . NGS was available for 8/17 TRMN-PARPi and revealed mutations in DDR genes in 7/8 patients (6 patients with TP53 mutation, 2 with PPM1D mutation). For 3 patients, we had samples from OC stage, before PARPi administration. We found that mutations from TRMN stage were present at lower frequency, confirming clonal selection by PARPi treatment (Figure 1c). Conclusions Here we described, for the first time, a cohort of TRMN patients previously treated with PARPi for an OC. Intriguingly, most of these TRMN occurred with a short latency at the end of PARPi treatment, with unfavorable cytogenetic and very short OS. Moreover, we found a very high percentage of CH involved in the DDR pathway (62%) in patients under PARPi treatment without TRMN suggesting a potential clonal selection which could lead ultimately to TRMN. PARPi are now indicated in 1rst line high grade OC regardless of BRCA status, which should expand indications. Benefit for OC patients is not questionable; however, caution will be warranted for patients with CH before PARPi treatment, especially implicating DDR mutations. Disclosures Etienne: Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-139971
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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    Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience
    American Society of Hematology ; 2010
    In:  Blood Vol. 115, No. 9 ( 2010-03-04), p. 1690-1696
    Details
    In: Blood, American Society of Hematology, Vol. 115, No. 9 ( 2010-03-04), p. 1690-1696
    Abstract: Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P 〈 .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 × 109/L (5000/μL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2009-07-233387
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 10
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    Is Arsenic Trioxide (ATO) Required in the Treatment of Standard Risk Newly Diagnosed APL? Analysis of a Randomized Trial (APL 2006) By the French Belgian Swiss APL Group
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 451-451
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 451-451
    Abstract: Background: ATO is very effective in the treatment of APL and recent results have shown that ATRA+ATO combinations (without CT) were at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, in press). However, access to ATO remains limited for frontline treatment of APL in most countries, which must mainly rely on ATRA+CT combination. In those combinations, investigators have suggested that the amount of CT could be reduced and the incidence of relapses further diminished by introducing ATRA (Sanz) or ATO (Powell) during consolidation cycles. In a randomized trial (APL 2006 trial), we compared for consolidation treatment (after ATRA CT induction treatment) ATO, ATRA and the "classical" Ara C in standard risk APL (ie with baseline WBC 〈 10G/L). Methods: Between 2006 and 2013 newly diagnosed APL patients (pts) 〈 70 years with WBC 〈 10 G/L , after an induction treatment consisting of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3, were randomized for consolidation between AraC, ATO and ATRA. The AraC group ( standard group) received a first consolidation course with, Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and a maintenance during two years with intermittent ATRA 15d/ 3 months and continuous 6 MP + MTX,). The ATO and ATRA groups received the same treatment as the AraC group, but AraC was replaced respectively by ATO 0.15 mg/Kg/d d1 to 25 and ATRA 45 mg/m2/d d1 to 15 for both consolidation courses. We present here results of an analysis made at the reference date January 1st 2014 in the 398 pts aged 〈 70 years with WBC 〈 10G/L included before 1/1/2012. The primary endpoint was event free survival (EFS) from CR achievement. Relapse, survival, side effects of the treatment and duration of hospitalization were secondary endpoints. Results: Among the 398 included pts, 7 were excluded for diagnosis error, 96% achieved CR, 12 (3%) had early death (from bleeding (n=1), sepsis (n=6), Thrombosis (n=4), cardiac arrest (n=1)) and 4 (1%) had resistant leukemia. 353 pts were randomized for consolidation (118, 118 and 117 in the AraC, ATO and ATRA arms, respectively). Pre-treatment characteristics were well balanced between the 3 consolidation groups. Overall, 4, 0, and 7 pts had relapsed (p=0.03) and 6, 5, and 5 pts (p=0.93) had died in CR in the AraC, ATO and ATRA consolidation groups, respectively. Causes of death in CR were sepsis (n=4) and hemorrhage (n=2), AML/MDS (n=5), relapse of a previous cancer (n=2), other (n=2). Two of the 6 deaths in CR related to myelosuppression occurred in each arm. Of the 5 patients who developed AML/MDS, 2, 1 and 2 had been treated in the AraC, ATO and ATRA arms, respectively. Five-year EFS from randomization was 90.8% [85.5; 96.5], 92.5% [87.6; 98.4] and 86.8% [79.7; 94.5] (p=0.52), 5y CIR was 3.89% [0.08 ; 7.69] , 0% [0 ; 0], 7.41% [1.96 ; 12.87] (p=0.03) and 5 year OS was 93.6% [89.1; 98.3]%, 92.8% [87.6; 98.4] % and 91.9% [85.4; 98.9] (p=NS), in the AraC, ATO and ATRA consolidation groups, respectively. Median time to ANC 〉 1 G/L after the first consolidation course was 24, 24 and 17 in the AraC, ATO and ATRA group, respectively (AraC vs ATO: p= 0.96; ATO vs ATRA: p 〈 0.0001). Similarly, time to ANC 〉 1 G/L after the second consolidation course was 23, 19 and 13 days (AraC vs ATO: p= 0.02; ATO vs ATRA: p 〈 0.0001). Median duration of hospitalization after the first and the second consolidation course were 32d, 29d, 32d (p= NS) and 30d, 17d, 15d in the AraC, ATO and ATRA group, respectively (p 〈 0.0001). Conclusion: Very high CR rates are now obtained in standard risk APL on a very large multicenter basis using classical ATRA and anthracycline based CT combinations, with very few relapses. On the other hand, our results strongly suggest that relapse rates observed with regimens without ATO, although they are low, can be significantly further reduced by addition of ATO. The Ida-ATRA consolidation regimen in particular, while carrying reduced toxicity, was associated with a relapse rate of 7.4%. Our results therefore advocate systematic introduction of ATO in the first line treatment of standard risk APL, but probably not concomitantly with CT, a situation where we found myelosuppression to be significant. Disclosures Guerci-Bresler: ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Vey:Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Deconinck:NOVARTIS: Other: Travel for international congress; PFIZER: Research Funding; CHUGAI: Other: Travel for international congress; ALEXION: Other: Travel for international congress; JANSSEN: Other: Travel for international congress; ROCHE: Research Funding; LFB loboratory: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.451.451
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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