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In: The Hematology Journal, Springer Science and Business Media LLC, Vol. 2, No. 2 ( 2001), p. 87-96

Type of Medium: Online Resource

ISSN: 1466-4860

URL: Article

DOI: 10.1038/sj.thj.6200086

Language: Unknown

Publisher: Springer Science and Business Media LLC

Publication Date: 2001

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 761-761

Abstract: In elderly patients with acute myeloid leukemia (AML) treated intensively, no improvement has been shown in the last 20 years. We performed a retrospective study in 847 patients over 60 years old, prospectively enrolled in 3 trials conducted in France between 1995 and 2005, with the aim to investigate prognostic factors for complete remission (CR) achievement and survival. Induction therapy consisted in the association of Idarubicin 8mg/m2 d1-5 and Cytarabine 100mg/m2 d1-7 (Group I, 339 patients) or the same drugs with the addition of lomustine (10mg\m2 orally at day 1)(Group II, 508 patients). Consolidation therapy consisted of anthracycline and cytarabine courses at lower doses, preceded or not by a first course with intermediate dose cytarabine. The patients’ characteristics were similar between the two groups concerning sex, WBC count, ECOG, and cytogenetics, yet patients were older in Group II versus Group I (55% versus 45% over 69 years of age, p 〈 0.0001).The CR rate was significantly higher for patients in Group II compared to Group I (67 % vs 57%, p= 0.002). The toxic death rate was not different between groups. In multivariate analysis, three good prognostic factors emerged for achieving complete remission: good or intermediate cytogenetics (p 〈 0.0001), ECOG 〈 2 (p 〈 0.0001), and adjunction of lomustine to induction chemotherapy (p=0.002). The median overall-survival was significantly improved for patients treated with lomustine (12.7± 2.2 months vs 8.7± 2.7 months, p=0.004). In multivariate analysis, five prognostic factors affected positively overall survival: adjunction of lomustine to induction chemotherapy (p 〈 0.0001), age 〈 69 years (p =0.001), ECOG 〈 2 (p =0.001), FAB other than AML0,6 or 7 (p = 0.004) and good or intermediate cytogenetics(p = 0.007). The median event-freesurvival was also improved for patients treated with lomustine (10.7± 2.2 months vs 7± 2.7 months, p=0.002). Event-free-survival was affected by the same prognostic factors as overall survival. We conclude that lomustine might be added in standard induction therapy as it allowed to obtain both better CR rate and survival in this retrospective study.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.761.761

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

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. 2691-2691

Abstract: The prognosis of poor risk AML in elderly pts justifies either supportive care only or investigational studies without obvious benefit of post-remission chemotherapies. A phase I study has demonstrated that the combination of azacitidine and lenalidomide is well-tolerated in AML with efficacy superior to that of single-agent therapy in higher-risk MDS (Sekeres JCO2010). The GOELAMS group investigated the efficacy of 12 maintenance cycles alternating monthly azacitidine (sc 75 mg/m²/d1-7) and lenalidomide (10mg/d1-21) every 28 days for pts in CR and compared the results to previous SA2002 and BGMT95 prospective trials which shared the same LIA induction followed by chemotherapy-based maintenance. Between 3/2011 and 2/2013, 117 pts from 27 centers (median age 69 yrs; 60-80, 9 pts ≥ 75) with previously untreated poor prognosis AML were included. Risk factors allowing inclusion were either: i) centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities), monosomal karyotype, t(6;9), del or – 5 or 7, and EVI1 or MLL rearrangement except for t(9;11); ii) preceding MDS (n=52) or iii) secondary leukemia occurring after previous cancer (n=37). Median WBC was 2.9 G/L (0.5-160), 19 pts had WBC 〉 30 G/L. Induction chemotherapy included lomustine 200 mg/m² po d1, Idarabucine 8 mg/m²/d (d1-5), cytarabine 100mg/m²/d CI (d1-7) and G-CSF (d15 to recovery). At the end of induction, CR (excluding CRp) was achieved in 56% (65 pts), 9% died from infection (n=6), cerebral hemorrhage (n=1) or multiorgan failure (n=4) and 35% (41pts) failed to achieve CR. Despite a trend towards a higher CR rate in pts without previous MDS (59% vs 48% CR), CR was not related to any of the risk factors studied. Median follow-up for survivors is 16 months (3-25). Monthly alternating azacitidine-lenalidomide maintenance therapy was started in 65 pts. Except for 1 pt who died during cycle1 of lenalidomide without any obvious explanation, tolerance was good. Median nadir of neutrophils and platelets was 1 and 96 G/L respectively. Grade 3/4 adverse events occurred in 6% of cycles and were due to infection, haemorrhage, hepatitis or fatigue (3%, 1%, 0.5%, 0.5% of cycles respectively). Median CR duration was 4.5 mo (1-23) and 40 pts relapsed. Allogeneic SCT with non myelo-ablative preparative regimen was performed in 4 pts less than 70 years in CR1: 1 is alive in relapse, 2 died of GVH and 1 is in continuous CR. Pts achieving CR had a median OS of 13 mo (95% CI 7.3-18.6), 54% being alive at 1 year and 15% at 2y. In refractory pts, the median OS was 7 mo (95% CI 2.8-11.2) with 32% alive at 1 year (P = 0.0001). OS and DFS reported in the current trial and compared to historical controls are described below: induction results are similar to those observed in the 128 poor risk cytogenetic pts of the previous SA2002/BGMT trials treated with the same LIA induction (CR 58%, early death 15%, failure 27%) but who received maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. No significant survival benefit was observed compared to pts with poor risk cytogenetics treated with chemotherapy maintenance in our previous trials. However, pts included in this trial have probably an even worse prognostic than those included in the GOELAMSSA2/BGMT95 trial which excluded AML secondary to MDS and previous cancers. This type of alternating azacitidine/lenalidomide maintenance improves OS and DFS of pts without poor risk cytogenetics (median DFS not reached and 19 mo) and could be randomly compared with conventional chemotherapy maintenance in AML secondary to MDS or cancer but also in older pts with intermediate risk cytogenetics.Median (95% CI)6mo1y2yOS maintenance aza-rev (117)9 mo (7.5-10.5)70%41%17%OS 2002/BGMT95 (128)6 mo (4.1-7.8)54%32%21%DFS maintenance aza-Rev (65)10 mo (2.5-17.4)61%49%8%DFS 2002/BGMT95 (74)9 mo (6.0-11.9)63%43%26%OS poor risk cytogenetic (83) vs other (33)8 mo vs NR P=0.000162% vs 83%27% vs 70%10% vs 60%OS previous cancer (37) vs no cancer (80)9 mo vs 9 mo68% vs 73%44% vs 40%24% vs 17%OS previous MDS (52) vs no MDS(64)12 mo vs 7 mo P=0.00177% vs 65%58% vs 26%27% vs 12%DFS poor risk cytogenetic (44) vs other (20)6 mo vs 19 mo P=0.00748% vs 84%33% vs 67%11% vs 28%DFS previous cancer (20) vs no K(45)8 mo vs 8 mo80% vs 61%46% vs 47%0% vs 13%DFS previous MDS (27) vs no MDS(38)15 mo vs 6 mo, P=0.0874% vs 48%59% vs 32%12% vs 0% Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2691.2691

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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. 136, No. Supplement 1 ( 2020-11-5), p. 18-19

Abstract: Background: A European Marketing Authorization Application for ivosidenib (IVO) is currently under review for the indication of mutant isocitrate dehydrogenase 1 (mIDH1) R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) in adult patients (pts) who have received ≥ 2 prior regimens, including ≥ 1 standard intensive chemotherapy (IC) regimen, or are not candidates for IC and have received ≥ 1 prior non-intensive regimen. IVO is an oral, potent, targeted inhibitor of mIDH1 and was approved by the FDA for the treatment of mIDH1 R/R AML in 2018, and in newly diagnosed AML in adults ≥ 75 years of age or pts ineligible for IC in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study. Aims: To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, UK, and Spain. Methods: Individual pt data from Arm 1+ of the AG120-C-001 study (n = 159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n = 127) and the RWD (n = 148). A medical review was conducted to identify Arm 1+ IVO pts in the AG120-C-001 study and HC pts who fell within the proposed EU indication. Treatment with IVO was compared with the most recent therapy received by HC pts. HC pts treated with IC as their most recent therapy were excluded, as IVO pts, based on the AG120-C-001 study's eligibility criteria, were not considered candidates for IC. Propensity score-based matching/weighting methods were used to adjust for imbalances in baseline prognostic factors between the 2 cohorts (optimal full matching and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 6 baseline prognostic factors for estimation of propensity scores (age, history of hematopoietic stem cell transplantation, number of prior regimens for AML, nature of AML, cytogenetic risk, and primary refractory status). Balance between populations was assessed pre- and post-match via comparison of (weighted) standardized differences (SDs) for each covariate. Time-to-event data were summarized via Kaplan-Meier (KM) estimators with 2-sided 95% confidence intervals (CI). Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HR) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Complete remission (CR) rates were also compared between IVO pts and RWD non-IC HC pts (AMLSG pts were excluded as the response data did not allow for identification of CRs distinct from other response types). Results: One hundred and nine IVO pts and 60 HC pts fell within the proposed EU indication. The IPTW-matched dataset was selected for analysis, as it more strongly minimized the absolute weighted SDs between cohorts as compared with optimal full matching, with all SDs & lt; 0.05. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with IVO compared with 2.9 mo (95% CI: 1.9, 4.5) in the HC pts. The HR for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favor of IVO (p & lt; 0.0001). There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). Conclusion: IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population. Disclosures Paschka: Amgen: Other; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Astex Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy, Speakers Bureau; BerGenBio ASA: Research Funding. Dombret:Novartis: Consultancy; Cellectis: Consultancy; Sunesis: Consultancy; Abbvie: Consultancy; Immunogen: Consultancy; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shire: Honoraria; Otsuka: Consultancy, Honoraria; Menarini: Honoraria; Daiichi Sankyo: Consultancy, Other: travel, accommodation expenses; Incyte: Consultancy, Other: travel, accommodation expenses; Celyad: Consultancy. Montesinos Fernandez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Kreuzer:Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Grifols: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Hexal: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Biotest: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau. Heuser:Karyopharm: Research Funding; Janssen: Consultancy; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Bayer: Consultancy, Research Funding; PriME Oncology: Honoraria. Metzeler:Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Astellas: Honoraria. Quesnel:Abbvie: Other: travel expenses; Daichii Sankyo: Other: travel expenses, Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. De Botton:Pierre Fabre: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Celgene: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria. Döhner:Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Astellas Pharma: Consultancy; Astex Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Agios: Consultancy; Novartis: Honoraria, Research Funding; Abbvie: Consultancy. Milkovich:RJM Group LLC: Current Employment. Reitan:RJM Group LLC: Current Employment. MacDonald:IQVIA: Current Employment. Casso:IQVIA: Current Employment. Storm:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Liu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Kapsalis:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Attar:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Döhner:Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Sunesis: Other, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136957

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2387-2387

Abstract: We have identified FOXC1 gene as being over-expressed in more than 50% of AML patients (pts) with normal karyotype when compared to normal hematopoietic cells in microarray analysis. Using RQ-PCR, we validated this finding and assessed the prognostic value, at diagnosis, of FOXC1 expression in a series of 142 adult AML pts (AML0 to AML6) followed at our institution. At diagnosis, pts median age was 62 years. Cytogenetics were available for 136 pts (MRC low-risk n=25 [AML3 n=12, CBF-AML n=13], intermediate-risk n=79, high-risk n=32). NPM1/Flt3ITD status was available for 129 pts (NPM1+/Flt3ITD– n=26, Flt3ITD+ n=18, NPM1–/Flt3ITD– n=85), and WT1 expression for all pts. Ninety-three pts received induction chemotherapy. Allogeneic SCT was performed in 21 pts. PCR results were compared to FOXC1 expression in K562 (100%). Results: FOXC1 expression level was higher in AML pts (median signal 152%; 25–75th percentiles 32–1036%; range 3–25280%) than in normal blood mononuclear cells (n=10; median signal 16%; 25–75th percentiles 14–26%), marrow cells (n=21; median signal 24%; 25–75th percentiles 16–42%)(p & lt;.001), as well as in cord blood BFU-E, CFU-E, CFU-G /-GM, and mononuclear cells (Signals & lt;25%; p & lt;.001). FOXC1 expression level was lower in AML3 than in other AML (p & lt;.001). Patients with low-risk cytogenetics had a similar profile (p & lt;.001), none belonging to the higher quartile Q4 (p=.001). Conversely, pts with high-risk cytogenetics more frequently belonged to Q4 (p=.025), especially those with monosomy 7 (p=.018). FOXC1 expression level was higher in NPM1+/Flt3ITD– pts than in those with other genotypes (p & lt;.001), and less frequently belonged to Q1 (p=.039). In pts with intermediate-risk cytogenetics (n=78), FOXC1 remained expressed at a higher level in NPM1+/Flt3ITD– pts than in other pts (median signals 440% vs 80%; p & lt;.003). In pts with intermediate-risk cytogenetics receiving induction chemotherapy (n=57), those within Q1 had a worse 5-year survival (0% vs 58%; p=.038 - RR, 3.05; 95%CI, 1.03–9.04) and EFS (0% vs 44%, see Figure), with a higher relapse incidence (66% vs 32%, p & lt;.02) and a lower DFS (34% vs 67%, p & lt;.02) at 5 years from CR1. Induction failures were also more frequent in Q1 (3/12 vs 1/42, p & lt;.03). No usual prognostic factors, such as NPM1/Flt3ITD status, were able to predict the outcome of our pts. Finally, a sequential MRD study showed that FOXC1 expression level correlated to disease evolution after induction or SCT (persisting CR, relapses). Conclusion: FOXC1 expression level appears to be a useful new prognostic marker in adult AML pts with intermediate-risk cytogenetics. Main covariates associated with FOXC1expression Covariates % of patients in Q1 (S & lt;32%) Median Signal (% / K562) % of patients in Q4 (S & gt;1036%) AML3 75% 16% 0% Other FAB AML 20% 205% 26% Low R KaryoT 44% 48% 0% Interm R KaryoT 19% 183% 25% High R KaryoT 22% 295% 37% Monosomy 7 18% 1258% 55% Normal KaryoT 10% 225% 31% NPM1+/Flt3ITD– 8% 917% 44% Other genotypes 28% 97% 19% Figure Figure

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.2387.2387

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 890-890

Abstract: Abstract 890 Background: While, with the combination of ATRA and anthracycline-based chemotherapy, 90–95% of APL pts included in APL clinical trials achieve complete remission (CR), it has been suggested that the actual early death (ED) rate may be as high as 15–17%, many pts being unable to enter clinical trials (Park JH, Blood 2011, Lehmann S, Leukemia. 2011 ). In some cases, an important delay in starting ATRA was also incriminated in ED (Altman, Blood 2011). We assessed the early outcome of newly diagnosed APL pts diagnosed in 16 large French centers during a period of 5 years, included or not in a clinical trial. Methods: 16 French University hospitals retrospectively provided data on all their APL pts diagnosed between Dec 2006 and Dec 2011, included or not in APL 2006 trial, the only active French APL trial during that period, which randomly assessed the role of ATO and ATRA during consolidation treatment, after ATRA – anthracycline based chemotherapy induction, and which had no upper age limit for inclusions. Every effort was made to collect all cases, by checking all APL diagnoses made in the lab and including pts admitted directly to ICU or to departments other than that of hematology, to avoid any bias. Intervals between first blood count, hospital admission and ATRA onset were particularly analyzed. ED was defined as death within 30 days of admission, irrespective of its cause. Results: 355 cases of newly diagnosed APL were seen during that period: 52% men, median age 52 years (range 16 –87). 26% of the pts had WBC 〉 10 G/L. 65.6% pts were included in APL 2006 trial and 34.4% not included. Reasons for non-inclusion in APL 2006 trial were: 32 patients refusing or unable to give consent (9%), 20 initial admissions in ICU (5.6%), 20 older age and/or comorbidities (5.6%), 8 previous cancer (2.3%), 11 contraindications to anthracyclines (3.1%), 5 other exclusion criteria (pregnancy, HIV, poor socioeconomic conditions) (1.4%), 2 deaths before ATRA onset (0.6%), 2 CNS bleeding at admission (0.6%) and 22 unknown reasons (6.2%). Pts not included were characterized by older age (median 62 vs 48 y, p 〈 0.0001) but a similar proportion of pts with high WBC (31% vs 24%,p=0.16). 20/33 (61%) pts aged ≥ 75 and 19/26 (73%) pts initially admitted in ICU were not included in APL 2006 trial. Median interval from first abnormal blood count to hospitalization was 〈 1 day (1 d and 〉 1 d in 20% and 22% pts, respectively), from hospitalization to ATRA onset 〈 1 day (1 d and 〉 1 d in 24.5% and 25% pts respectively) and from bone marrow aspirate to ATRA onset 〈 1 day ( 〈 1 d, 1 d, and 〉 1d in 66%, 19%, 15% pts respectively), without significant difference between pts included and not included in APL 2006. 316 (89.8%) pts reached CR, 1 had resistant leukemia and 35 pts (9.9%) had ED. 8 of the 35 ED (2.2% of the whole population) occurred before ATRA onset. Causes of ED in pts who received ATRA were: differentiation syndrome (DS) (n=5), CNS bleeding (n=4), sepsis (n=7), myocardial infarction (n=2), multiple organ failure (n=4), uncertain (n=5). No significant differences in the incidence of ED were seen based on the various intervals analyzed (from first blood count to hospital admission, admission to ATRA onset, BM aspirate to ATRA onset). In particular, ATRA onset within 〈 1, 1 and 〉 1 day of hospitalization was associated with ED rates of 9.4%, 7% and 8%, respectively (p=0.961). ED was seen in 3% (7/233) of pts included in APL 2006 trial and 23% (28/122) of non protocol pts (p 〈 0.0001), and the CR rate was 97% and 77% in APL trial and non protocol pts (p 〈 0.0001). In particular, in pts aged ≥ 75, the ED rate was 0% and 30% in protocol and non protocol pts, respectively (p=0.06). Still, overall, 16/26 (61.5%) of the pts admitted directly in ICU, 27/33 (82%) of the pts aged ≥ 75, and 77/92 (83.7%) of the pts with WBC 〉 10G/L achieved CR. Conclusions: (1) A large majority of APL pts are rapidly admitted to hospital and rapidly treated with ATRA in France, with an overall CR rate of 89.8%. (2) One third of the pts are not included in clinical trials, especially due to their age or critical condition, and their outcome is less favorable than that of protocol patients (77% versus 97% CR). On the other hand, 61.5% of the pts directly admitted to ICU and 82% of those aged ≥ 75 y achieved CR. (3) Our overall early death rate (9.9%) appears inferior to those published in several recent studies. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.890.890

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1719-1719

Abstract: Abstract 1719 Background Prognostic of IPSS high and int-2 risk MDS after azacitidine failure or relapse is very poor, with a median survival 〈 6 months (Prebet, JCO 2011). We previously showed that Erlotinib (ERLO), an oral inhibitor of EGF-R tyrosine kinase approved for the treatment of several solid tumors, also has “off target” in vitro effects in myeloid leukemic cell lines and primary blast cells of higher risk MDS and AML (Boehrer, Blood 2008). ERLO induced, cell cycle arrest, myeloid differentiation, apoptosis and also reduced the growth of xenografted human AML cells. We therefore assessed safety and efficacy of ERLO in higher risk MDS with AZA failure in a phase I/II trial. Methods This trial (NCT 01085838), conducted by the GFM, had the following inclusion criteria: (1) MDS according to WHO classification (also including RAEBt /AML with 20–30% blasts), (2) IPSS Int-2 or High, (3) marrow blasts 〉 10% and 〈 30% (4) no response to treatment with AZA for at least 6 cycles, or relapse after a response. Patients with CMML, prior history of MPN, HIV infection, concomitant treatment with CYP3A4 inducers or inhibitors were excluded. The phase I part was a 2 cohort escalating dose study of ERLO at 100 mg/d in the first cohort, and 150 mg/d in the second. Response was evaluated according to IWG2006 criteria after 12 weeks of treatment. In the absence of limiting toxicity or progression at 12 weeks, treatment was to be continued until progression. Results Between July 2010 and July 2012, 29 patients (19M, 10F) were included in 9 centers. Median age was 77 years (range 65–85). Median number of cycles of AZA before inclusion was 18 (5–41). Before AZA, 6 pts had received intensive chemotherapy (with 3 CR, 1 PR and 2 failures) and 1 Lenalidomide, without response. At inclusion, 17 pts had RAEB-2 and 12 had RAEB-t/AML with 20–30% blasts. IPSS cytogenetic risk was poor in 6 pts (21%) including 5 complex, intermediate in 9 pts (31%) and good in 8 pts (38%, all normal karyotype), while 6 pts had cytogenetic failure. During the phase I part, five patients received ERLO at 100 mg/day, and 5 pts ERLO at 150 mg/d. After review of toxicities by the independent DSMB, the ERLO dose of 150 mg/d was retained for the phase II part, that included 19 patients, of who 7 had not yet completed 12 weeks of treatment and were too early for evaluation. Overall, 22 patients were evaluable (including 6 AZA failure and 16 relapses after response to AZA) 5 of them had early death (before week 12) due to disease progression (n=2), sepsis (n=3) and 9 additional pts stopped treatment before week 12 due to grade 2 skin rash (n=2), bleeding (n=1), fatigue (n=1), investigator's decision(n=1), consent withdrawal (n=1), disease progression (n=3). Three patients, ie 13.6% of the 22 evaluable, and 37.5% of the 8 pts who received at least 12 weeks of treatment achieved IWG2006 response (2 at 100mg/d and 1 at 150 mg/d) including 1 marrow CR, 2 hematological improvement (1 HI E and 1 HI P). Six pts had stable disease without HI, and 13 pts progressed. All 3 responders had RAEB-2, with normal, int and failed karyotype, respectively. Two had received intensive chemotherapy before AZA (with 1CR and 1PR), 2 had relapsed after AZA response and 1 had not responded to AZA. Response duration was 3.4 (pt with marrow CR) 5.3 and 11.7+ months, respectively. Survival of the 3 responders from inclusion was 6.1,15 and 14.5 + months, respectively. Median OS from inclusion was 4 months. In the 100 mg/day cohort, 7 SAE occurred (3 sepsis, 1 grade I liver toxicity, 1 FUO and 1 grade III anorexia). No hematological toxicity was described and no DLT was seen. In the 150 mg cohort, 5 SAE occurred (3 sepsis, 1 bleeding and 1 grade III diarrhea). The most common toxicities reported were grade I rash (80%) and grade I diarrhea (30%). Bone marrow cells were collected in all the patients at inclusion and at week 12, and study of in vivo ex vivo correlations is in progress. Conclusion Erlotinib at 100 to 150 mg/ d is well tolerated in higher risk MDS resistant to AZA. A few (13.6% in the whole cohort ) significant responses occurred including 1 marrow CR, 1 HI E and 1 HI P. Based on our previous in vitro work showing that ERLO can potentiate the effect of AZA on MDS and AML cells, particularly by inhibiting drug efflux via ABC transporters. (Lainey et al, ASH2010,abstract 974,) combinations of AZA and ERLO could be considered in the treatment of higher risk MDS. Disclosures: Off Label Use: Erlotinib is approved to treat non small cell lung cancer and pancreatic cancer.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.1719.1719

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1983-1983

Abstract: In an attempt to improve the outcome of acute myeloid leukemia in older patients, we performed a multicenter randomized trial evaluating the possible benefit of androgens during post remission therapy. All patients received the ICL regimen as induction (Idarubicin, 8mg/m2 d1–5; Cytarabine, 100mg/m2 d1–7 and Lomustine, 200mg/m2 d1). All patients were randomized at the time of diagnosis to receive, after achieving CR or PR, a maintenance therapy including or not androgens. Maintenance therapy consisted of 6 courses of reinduction with idarubicin (8mg/m2 d1) and cytarabine (100mg/m2d1–5, subcutaneously) every 3 months, and, between these courses, a continuous regimen of methotrexate and 6-mercaptopurine. Patients randomized with androgens additionally received 10 to 20 mg according to body weigh of norethandrolone daily from CR/PR on, for up to 2 years. Between June 2002 and January 2005, 330 patients aged ≥ 60 years (median 70 yrs, range 60–86) were included. CR, PR, failure and death rates after induction were 69 %, 6%, 9% and 15% respectively. The median follow-up for the 330 patients was 26 months. Among the 249 patients who achieved remission, 119 had been randomized with norethandrolone and 130 without. The 2 arms were balanced according to age, sex-ratio, performance status, FAB, WBC as well as platelets counts, peripheral blood and bone marrow blasts counts and cytogenetic groups (low risk: t(8;21), inv(16); high risk: del(5), del(7), del(11q), complex karyotype; standard-risk: normal karyotype and other aberrations). Differences in CR rates were only related to the latter parameter of cytogenetic features (P = 0.005). For the whole cohort of patients DFS at 3-years was 23±3% (median 13 months) and OS at 3 years was 29±3% (median 15 months). For patients who achieved CR or PR and had been randomized, the addition of androgens did not influence either DFS (P = 0.6) or OS (P = 0. 9), even when considering age groups, high/low WBC, or cytogenetic features. In conclusion, the ICL regimen followed by six reinductions and two years maintenance therapy induce high CR rates and improve OS and DFS. However the addition of androgens did not decrease the relapse rate.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.1983.1983

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: American Journal of Hematology, Wiley, Vol. 98, No. 6 ( 2023-06), p. 922-931

Abstract: The aim of this study was to evaluate how comorbidities and molecular landscape relate to outcome in patients with acute myeloid leukemia (AML) aged 60 years or older who received intensive induction therapy. In 91 patients, 323 mutations were identified in 77 genes by next‐generation sequencing, with a median of four mutations per patient, with NPM1 , FLT3 , TET2 , and DNMT3A being the most frequently mutated genes. A multistate model identified FLT3 , IDH2 , RUNX1 , and TET2 mutations as associated with a higher likelihood of achieving complete remission while STAG2 mutations were associated with primary refractory disease, and DNMT3A , FLT3 , IDH2 , and TP53 mutations with mortality after relapse. Ferrara unfitness criteria and performance status were the best predictors of short‐term outcome (area under the curve = 82 for 2‐month survival for both parameters), whereas genomic classifications better predicted long‐term outcome, with the Patel risk stratification performing the best over the 5‐year follow‐up period (C‐index = 0.63 for event‐free and overall survival). We show that most genomic prognostic classifications, mainly used in younger patients, are useful for classifying older patients, but to a lesser extent, because of different mutational profiles. Specific prognostic classifications, incorporating performance status, comorbidities, and cytogenetic/molecular data, should be specifically designed for patients over 60 years.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v98.6

DOI: 10.1002/ajh.26917

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 1492749-4