Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2171-2171

Abstract: Abstract 2171 Background: Our group (JCO, 1992 10:1430; JCO 2003,21:2123) and others have reported tAPL to occur at increased frequency (from 5% of APL between 1984 and 1993 to 22% between 1994 and 2000 in our experience), generally less than 3 years after a primary neoplasm (mainly breast carcinoma) treated with the combination of anthracyclines (anthr) and cyclophosphamide (CY), radiotherapy (RT) and less often VP 16, but our last published series analyzed patients (pts) diagnosed before 2001. In addition, characteristics and outcome of tAPL are considered similar to those of de novo APL, but all reported comparisons were retrospective. We took advantage of our current multicenter APL 2006 trial, which includes both de novo and tAPL, to analyze possible recent changes in etiological factors of tAPL cases, and to prospectively compare them with de novo APL. Methods: In APL 2006 trial, pts 〈 70 years with WBC 〈 10 G/l, received ATRA+Idarubicin+AraC for induction, followed by 2 consolidation courses with (randomized) Ida+AraC, ida+ATO or Ida+ATRA. Pts 〈 70 y with WBC 〉 10 G/l, received the same induction treatment, followed by 2 consolidation courses with (randomized) ida+AraC or Ida+AraC+ATO. Pts 〉 70y received the same induction course with reduced dose of Ida and two consolidation courses (Ida+ATO and ATO+ATRA). All patients received 2 y maintenance therapy combining continuous 6MP+ MTX and intermittent ATRA. Results: Between Nov 2006 and March 2010, 280 pts entered the trial, including 42 (15 %) tAPL. By comparison to our tAPL diagnosed before 2001 (JCO 2003, 21, 2123) the primary tumor was less often breast carcinoma (35.7% vs 56.6%, p=0.03), and more often prostate carcinoma (26.2% vs 4.7%; p 〈 10-3) and other solid tumors (45.2% vs 18.8% p=0.02). Treatment of the primary tumor, in APL 2006 trial cases and tAPL diagnosed before 2001, respectively, included chemotherapy (CT) alone in 21.4% vs 27.3% pts (p= 0.535), RT alone in 40.5% vs 25.4% pts (p= 0.077) and RT+CT in 28.6% vs 47.2%(p= 0.044), and, in pts who received CT, at least one alkylating agent in 90.5% vs 86% pts (p=ns), at least one topo II inhibitor in 61.9% (including anthr in 47.6% and VP 16 in 14.2%) vs 77% pts (including anthr in 37.9% and VP 16 in 24.1%), and including mitoxantrone in 0% vs in 36.4% pts (p 〈 10-3). Hormone therapy was used in 42.9% (including antioestrogen (n=7), aromatase inhibitors (n=7) GnRH analogues (n=4), and anti androgens (n=4)) vs 24.5% (no details available), resp. Median interval from primary tumor to tAPL was 48 months (range 6.9 to 299) in tAPL included APL 2006 trial, compared to 25 months in our previous tAPL series. In APL 2006 trial, characteristics of tAPL were similar to those of de novo APL, with regards to WBC count (21.4% WBC 〉 10 G/l vs. 22.3% in de novo APL, respectively) and M3 variant (14% in the 2 groups). However, tAPL were older (mean 60.2y vs 48.7y in de novo cases, p 〈 0.0001) and had a higher frequency of bcr3 breakpoint (36% vs 54%, p=0.015). The CR rate was 97.6% (41/42) in tAPL and 93.4% in de novo APL (p=0.48). The 18-month cumulative incidence of relapse was 0% and 1.2% in tAPL and de novo APL respectively (p=0.43). 18 months OS was 96.4% and 97.0%, respectively (p=0.83, log-rank test). The 18 month rate of death in CR was 3.6% in both tAPL and de novo APL (p=0.97), Conclusion: In this series of recently diagnosed tAPL, by comparison to our tAPL diagnosed before 2001, the primary tumor was less often breast carcinoma and more often another solid tumor (especially prostate). A combination of CT and RT had been less often used, hormone therapy more often, and mitoxantrone had no more been used. Prospective comparison with de novo APL included in the same trial showed tAPL to be characterized by older age and more frequent bcr3 breakpoint, but there were no differences in outcome between the 2 subgroups Disclosures: 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.V116.21.2171.2171

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2608-2608

Abstract: Abstract 2608 Aim. CBF-AML is a favorable AML subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, respectively responsible for RUNX1-RUNX1T1 (CBFα) or CBFB-MYH11 (CBFβ) gene fusion. Nonetheless, relapse incidence may reach 30–40% in these patients. The tyrosine kinase (TK) receptor KIT is expressed in the vast majority of CBF-AML and activating KIT gene mutations, including exon 8 del/ins and exon 17 point mutations, have been reported in both CBF-AML subtypes. These mutations have been retrospectively associated with a higher risk of relapse. Dasatinib is a TK inhibitor active on both wild-type and mutant KIT isoforms. These observations led several groups to initiate prospective trials testing dasatinib/chemotherapy combinations in newly diagnosed CBF-AML patients. The aim of the present Phase 2 DASA-CBF trial (EudracCT 2006-00655-12) was to search for a positive signal by treating CBF-AML patients in first complete remission (CR), but with persistent or re-appearing molecular minimal residual disease (MRD), by the single-agent dasatinib. Prevention of further hematological relapse was the primary endpoint. Methods. Eligible patients (18–60y) had to have been previously enrolled and treated in the CBF-2006 study (Jourdan et al. this meeting). MRD was quantified by RQ-PCR and results were expressed as 100 × CBF fusion gene/cABL ratios. Patients in first CR were eligible if: 1) MRD ratio reduction less than 3-Log before the second consolidation cycle (refractory Mol-REF patients); or 2) MRD ratio re-increase more than 1-Log on two successive evaluations (relapsing Mol-REL patients). Patients with a sibling or unrelated donor and no contra-indication to allogeneic stem cell transplantation (SCT) were not eligible. Dasatinib was administered orally at 140 mg once daily for a total duration of 12 months. In case of grade 3 adverse event (AE), treatment was discontinuated until AE resolution to grade 0–1. In case of grade 4 AE or AE reappearance, dose reduction to 100 mg/d was allowed. Dose escalation to 90 mg bid was allowed in case of stable or increasing MRD after 2 months of therapy without toxicity. Results. Between June 2008 and June 2011, 26 CBF-AML patients (median age, 44y) were included. They were 12 CBFα patients (6 Mol-REF, 6 Mol-REL) and 14 CBFβ patients (12 Mol-REF, 2 Mol-REL). Seven patients had a KIT mutation (4 exon 8 and 3 exon 17; 3 CBFα and 4 CBFβ). The median time between CR achievement and DASA-CBF enrollment was 161 days (106–406) in Mol-REF patients and 413 days (167–530) in Mol-REL patients. Overall, dasatinib was well tolerated. Two grade 3 AEs (hypertension, headache) led to dasatinib dose reduction without further reoccurrence. Dose escalation was performed in two patients. With the exception of one patient (without KIT mutation) still alive in CR1 at 929 days, 7 of the 8 Mol-REL patients had rapid hematological relapse under dasatinib treatment after a median time of 60 days (52–120). In the 18 Mol-REF patients, the probability of persistent hematological remission was 65% (95% CI, 38–82) at 12 months and 45% (95% CI, 20–67) at 24 months, with a trend for shorter remission duration in the 6 patients with KIT mutation (P=0.07). These 18 Mol-REF patients were compared to the 37 other Mol-REF patients from the CBF-2006 trial not enrolled in the DASA-CBF trial (9 SCT in CR1, 28 without further therapy). Both series were comparable in terms of age, WBC, baseline fusion transcript ratio, MRD ratio Log-reduction after induction and first HDAC consolidation, as well as additional cytogenetic anomalies and KIT, FLT3 and RAS gene mutations. Despite dasatinib treatment, the probability of persistent hematological remission was not higher in the 18 DASA-CBF patients than in the 28 patients who received no further therapy (45% versus 53% at 24 months, P=0.91). Conversely, only one hematological relapse was observed in the 9 patients who received SCT in CR1, the remaining 8 patients being alive in continuous CR. Conclusion. This Phase 2 trial failed to show a significant effect of single-agent dasatinib in the prevention of hematological relapse in CBF-AML patients in first CR after standard therapy, but at high risk of relapse because of persistent or re-appearing MRD. Moreover, no trend towards a preferential effect was observed in KIT mutated patients. This observation does not preclude any dasatinib activity in CBF-AML patients when combined with conventional chemotherapy. Disclosures: Off Label Use: Dasatinib is not approved for AML patients. Mohamed:Bristol-Myers Squibb: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.2608.2608

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 876-876

Abstract: Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients. Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen. Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including "7+3" with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months. Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age & lt;50 years, de novo AML and relapse status. Among the 191 responders, 110 received additional courses of chemotherapy, 69 with GO. Main reason to not receive additional course (with or without GO) was allo-HSCT project. In the whole population, median overall survival (OS) after day 1 of treatment with GO was 11.2 months. In the population of responders, median OS after response was 20.4 months. In multivariate analysis, longer survival was associated with age & lt; 50 years, de novo AML and favorable ELN group. Cumulative incidence of relapse at 24 months after response was 46%. One hundred and forty-seven patients received allo-HSCT, including 122 responders after GO-based regimen and 25 patients in treatment failure. Cumulative incidence of allo-HSCT at 18 months was 48%. Four-year OS was 48% in transplanted patients versus 19% in non-transplanted patients (Figure 1). Regarding safety of GO-based regimen, early deaths occurred within & lt;30 days after the first dose of GO in 14 patients, and within & lt;60 days in 35 patients. Myelosuppression was observed in all patients. Mean duration of thrombocytopenia & lt;100 G/L was 35 days in responders. Bleeding grade 3 or more was observed in 22 patients (7%). Infection grade 3 or more was observed in 112 patients (30%). Sinusoidal obstruction syndrome (SOS) after GO treatment was reported in 6 patients, resolving in 4 of them. Four cases of fatal SOS were reported after allo-HSCT. Toxic deaths, i.e., not related to worsening leukemia, were reported in 20 patients after the first course of chemotherapy, 3 after additional courses and 33 after allo-HSCT. Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-145184

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. 132, No. Supplement 1 ( 2018-11-29), p. 80-80

Abstract: Background: Characteristics and outcome of older patients (pts) with acute promyelocytic leukemia (APL) are unclear due to lack of clinical data. Aims: To describe a large series of older APL pts and compare outcome according to treatment strategy. Methods: We retrospectively studied 475 APL pts (median age, 73.8 yrs; range, 70-90.3 yrs), treated between 1990 and 2018 within four study groups/institutions of the US and Europe (Acute Leukemia French Association, n=228; Programa Espanol de Tratamientos en Hematologia, n=211; Study Alliance Leukemia, n=28; Johns Hopkins School of Medicine, Baltimore, n=8). APL was confirmed either by cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction. For analysis, pts were grouped according to treatment: i) chemotherapy/all-trans retinoic acid (CTX/ATRA, n=260; consisting of daunorubicin/idarubicin and ATRA for induction and different CTXs+ATRA for consolidation), ii) ATO/ATRA±CTX, n=177 (according to Lo-Coco F, et al. NEJM, 2013, n=23 or CTX/ATO/ATRA, n=154), iii) less intensive therapy, n=26 (reduced CTX, n=2 or ATRA only, n=24) and iv) no treatment/unknown, n=12. Results: Median white blood cell (WBC) and platelet counts at diagnosis were 1.5/nl (range, 0.1-242/nl) and 37/nl (range, 2-261/nl), respectively. Two-hundred twenty-nine pts (48%) were female. Cytogenetic analysis was available in 408 pts and 85 (21%) had additional abnormalities. BCR3 was positive in 138 (44%) of 316 available pts. Only 15 (22%) of 69 tested pts were FLT3-ITD positive. One hundred (22%) of 464 pts had a WBC count 〉 10/nl. Median WBC was significantly lower (P 〈 0.001) in the ATO/ATRA±CTX group (1.2/nl) as compared to the CTX/ATRA (2.05/nl) or less intensive (2.8/nl) group. Median age was comparable in CTX/ATRA (73.5 yrs) and ATO/ATRA±CTX (73.6 yrs) but significantly higher (P 〈 0.001) in the less intensive group (79.6 yrs). Median platelet counts were comparable (P=0.08) in the three groups (CTX/ATRA, 34.5/nl; ATO/ATRA±CTX, 41/nl; less intensive, 39/nl). Response data were available in 459 (97%) pts. Complete remission (CR) after induction therapy was achieved in 75% (194/259) of the CTX/ATRA group, in 93% (162/174) of the ATO/ATRA±CTX group, and in 50% (13/26) of the less intensive group. Two pts of the CTX/ATRA group and one patient after ATRA only were refractory. Early death rates were 24% (n=63) after CTX/ATRA, 7% (n=12) after ATO/ATRA±CTX and 46% (n=12) in the less intensive group. A logistic regression model revealed age above 75 yrs (odds ratio [OR], 0.53; P=0.02) higher WBC (OR, 0.35; P 〈 0.001), less intensive treatment (OR, 0.46; P=0.08) and therapy with ATO/ATRA±CTX (OR, 4.2; P 〈 0.001) as significant factors for achievement of a CR. Median follow-up was 4.7 yrs (95%-CI, 4.2-5.4 yrs) and 5-yrs overall survival (OS) 62% (95%-CI, 57-67%). Treatment with ATO/ATRA±CTX was associated with significantly higher 5-yrs relapse-free (RFS; 96% [95%-CI, 92-99%] vs. 88% [95%-CI, 83-93%] ; P=0.007) and OS rates (78% [95%-CI, 72-85] vs. 58% [95%-CI, 52-65%] ; P 〈 0.001) as compared to CTX/ATRA. Of note, higher WBC count ( 〉 10/nl) was associated with an inferior RFS in CTX/ATRA (P 〈 0.001), but not in ATO/ATRA±CTX (P=0.47). When restricting the analysis according to treatment period after the year 2000, ATO/ATRA±CTX was still associated with a significant better RFS (P=0.05) and OS (P 〈 0.001) as compared to CTX/ATRA. Overall, only five pts relapsed after ATO/ATRA±CTX as compared to 33 after CTX/ATRA. As expected, higher WBC ( 〉 10/nl; hazard ratio [HR], 2.36; P 〈 0.001), age 〉 75 yrs (HR, 2.07; P 〈 0.001) and therapy with ATO/ATRA±CTX (HR, 0.48; P 〈 0.001) were significant factors for OS. Conclusions: The ATO-based regimen for first line treatment of elderly APL pts was associated with excellent and sustained response rates. Our data demonstrate the important potential of ATO/ATRA in the primary management of older APL pts. Disclosures Fenaux: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111768

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. 134, No. Supplement_1 ( 2019-11-13), p. 1416-1416

Abstract: Background : Point mutations in isocitrate dehydrogenase (IDH) genes are seen in 20% of adult patients (pts) with acute myeloid leukemia (AML). Prognostic significance of each IDH1/2 mutation (mut) analyzed with co-occurring mutations treated with intensive chemotherapy (IC) remains inconsistent, particularly with the advent of IDH inhibitors. Furthermore, the role of allogeneic stem cell transplantation (SCT) in IDH-mutated without favorable-risk features is not known. Patients & Methods: Between 2009 and 2016, 262 pts with IDH1/2 mutated AML (101 IDH1mut, 115 IDH2R140Qmutand 46 IDH2R172mut) were treated with IC in younger ALFA-0702 (NCT00932412, n = 133) and older ALFA-1200 (NCT01966497, n = 129) prospective trials. Median age was 50 [42-54] and 67 y [64-71] , respectively (resp). Targeted 37-gene next-generation sequencing (NGS) information was available for all pts. According to ELN 2010 classification, non-favorable CR/CRp pts were eligible for SCT if they had a sibling or matched unrelated donor. Correlation between IDHmutand covariates was realized by Pearson correlation coefficient and point biserial correlation for continuous and dichotomic variables, resp. Impact on response and survival was assessed for all covariates present in at least 10% of patients. SCT was considered as a time-dependent variable. Informative variables selected by LASSO were included in multivariate logistic regression for response and multivariate Cox model for survival. All analyses were stratified on the clinical trial. Results: IDH1 mut was significantly associated with NPM1mut(p=0.025), DNMT3Amut(p=0.009) and mutually exclusive with TET2mut(p=0.009). 80% (81/101) of IDH1 mutated pts achieved CR/CRp [96 % (46/48) if concomitant NPM1mut vs 66% (35/53) if not (p=0.0009)]. With a median FU of 39 months, overall median OS was not reached and median EFS was 15 months (Fig 1A). Presence of NPM1mutwas the only variable associated with longer OS (HR=0.33, p=0.001) and EFS (HR = 0.4, p = 0.001) in multivariate analysis. At 5 years, OS was estimated at 68% and 35% and EFS at 55% and 26%, resp (Fig 1B). Effect of concomitant NPM1mutwas reinforced in the absence of DNMT3Amut(HR=0.14, p=0.0006 and HR=0.16, p & lt;0.0001, for OS and EFS resp). At 5 years, EFS was estimated at 70% in IDH1+/NPM1+/DNMT3A- AML pts vs 30% for other IDH1+ AML pts (Fig 1B). IDH2R140Q mut was significantly associated with NPM1mut(p=0.0004) and SRSF2mut(p & lt;0.0001) and normal karyotype (p=0.002), but negatively correlated with complex karyotype (p=0.01). 91% (105/125) pts with IDH2R140Q mutated AML achieved CR/CRp [100 % (58/58) if concomitant NPM1mutvs 82% (47/57) if not (NS)]. With a median FU of 40 months, overall median OS was not reached and median EFS was 25 months (Fig 1A). Again, the presence of NPM1mutwas associated with a longer OS and EFS (HR=0.47, p=0.02 and HR= 0.24, p & lt;0.0001, resp). Presence of DNMT3Amutwas associated with shorter OS (HR = 2.1, p=0.02) and EFS (HR = 2, p=0.008) along with high WBC (HR = 1.9, p=0.005) for decreased EFS. At 5 years, OS was estimated at 67% in IDH2R140Q+/NPM1+ AML pts vs 40% in those with IDH2R140Q+/NPM1- AML. At 5 years, EFS was estimated at 56% vs 29% in these two subgroups, resp (Fig 1B). Again, the effect of concomitant NPM1mutwas reinforced in the absence of DNMT3Amut(HR = 0.26, p=0.0009 and HR = 0.15, p & lt;0.0001, for OS and EFS resp). At 5 years, EFS was estimated at 72% in IDH2R140Q+/NPM1+/DNMT3A- AML pts vs 29% in other IDH2R140Q+ AML pts (Fig 1C). IDH2R172K mut was significantly associated with DNMT3Amut(p=0.0004) and BCORmut(p & lt;0.001), as well as +11 (p=0.002), but negatively correlated with NPM1mut(p=0.001). 78% (36/46) pts with IDH2R172Kmutachieved CR/CRp. No genetic alteration was associated with outcome, perhaps due to limited number of pts. With a median FU of 43 months, overall median OS and EFS were 60 and 14 months, resp (Fig 1A). Finally, in non-favorable ELN 2010 pts (74, 74 and 46 with IDH1mut, IDH2R140Qmutand IDH2R172Kmut, resp), SCT in first CR only benefited to pts with IDH1mut(p=0.004 for OS) or with IDH2R172Kmut(p=0.03 for EFS). Conclusion: In a large prospective series, NPM1mutis the main better risk factor in the IDH1mutand IDH2R140Qmutsubgroups and may be used as stratification factor in clinical trials testing frontline specific IDH inhibitors with IC. Allogeneic SCT in first CR appears to improve the outcome of pts with non-favorable IDH1 or IDH2R172K mutated AML. Figure 1 Disclosures Micol: Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy. Thomas:ABBVIE: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria; PFIZER: Honoraria. Braun:Institut de Recherches Internationales Servier (IRIS): Research Funding. Ades:Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees. Berthon:PFIZER: Other: DISCLOSURE BOARD; JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD. Boissel:NOVARTIS: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Pigneux:Astellas: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Jazz: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Daichi: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dombret:CELGENE: Consultancy, Honoraria; AGIOS: Honoraria; Institut de Recherches Internationales Servier (IRIS): Research Funding. De Botton:Daiichi: Consultancy; Janssen: Consultancy; Agios: Consultancy, Research Funding; Astellas: Consultancy; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Forma: Consultancy, Research Funding; Syros: Consultancy; AbbVie: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Bayer: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-127082

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. 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

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

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

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 36 ( 2006-12-20), p. 5703-5710

Abstract: Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial. Patients and Methods Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/μL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/μL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/μL. Results Overall, 328 (96.5%) of 340 patients achieved complete remission (CR). In the AraC and the no AraC groups, the CR rates were 99% and 94% (P = .12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% and 15.9% (P = .011), the event-free survival (EFS) rates were 93.3% and 77.2% (P = .0021), and survival rates were 97.9% and 89.6% (P = .0066), respectively. In patients younger than age 60 years with WBC counts more than 10,000/μL, the CR, 2-year CIR, EFS, and survival rates were 97.3%, 2.9%, 89%, and 91.9%, respectively. Conclusion These results support a role for AraC in addition to ATRA and anthracyclines in the treatment of newly diagnosed APL, at least using DNR at the cumulative dose we used and with the consolidation and maintenance regimens we used.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2006.08.1596

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2006

detail.hit.zdb_id: 2005181-5

In: Cancer, Wiley, Vol. 121, No. 14 ( 2015-07-15), p. 2393-2399

Abstract: The current results suggest that, at least for secondary acute promyelocytic leukemia (APL), evolving strategies in the treatment of cancers have modified the primary tumors and the drugs involved in leukemogenesis, but without reducing their incidence. These findings also confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL.

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v121.14

DOI: 10.1002/cncr.29389

Language: English

Publisher: Wiley

Publication Date: 2015

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1