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In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 8 ( 2021-08), p. 2332-2345

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-01117-w

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 94, No. 4 ( 1999-08-15), p. 1192-1200

Abstract: All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA→CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment] ) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients ≤75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients ≤65 years of age and with an initial WBC count of ≤5,000/μL (n = 208) were randomized between ATRA→CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/μL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA →CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA→CT group (P = .04, relative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA→CT group (P = .1, RR = .62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P = .0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P= .02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who received maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V94.4.1192

Language: English

Publisher: American Society of Hematology

Publication Date: 1999

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 94, No. 4 ( 1999-08-15), p. 1192-1200

Abstract: All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA→CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment] ) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients ≤75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients ≤65 years of age and with an initial WBC count of ≤5,000/μL (n = 208) were randomized between ATRA→CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/μL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA →CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA→CT group (P = .04, relative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA→CT group (P = .1, RR = .62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P = .0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P= .02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who received maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V94.4.1192.416k07_1192_1200

Language: English

Publisher: American Society of Hematology

Publication Date: 1999

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 889-889

Abstract: Background Inhibitory Killer Immunoglobulin-like Receptors (KIR) negatively regulate Natural Killer (NK) cell-mediated killing of HLA class I-expressing tumors. Lack of KIR-HLA class I interactions has been associated with antitumor efficacy and increased survival in patients (pts) with AML in CR after haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). IPH2101, a fully human mAb designed to enhance antitumor effects of NK cells by blocking the major inhibitory HLA-C-specific KIR can be safely administered in elderly pts with AML (Vey, Blood 2012). Lirilumab is a 2nd generation anti-KIR mAb currently evaluated in multiple indications and combinations with encouraging preliminary results in combination with nivolumab in pts with squamous cell carcinoma of the head and neck (Leidner, SITC 2016). Here we report the results of a phase 2 trial with lirilumab as single agent in the maintenance therapy of elderly pts with AML in first CR. The objectives of this randomized phase 2 study were to determine if lirilumab could improve leukemia free survival (LFS) and to assess two dose schedules predicted from the phase 1 dose-escalation trial (Vey, ASCO 2015) to be associated with either continuous (CONT) or intermittent (INT) full KIR occupancy. Methods EFFIKIR was a randomized double-blind 3-arm placebo controlled trial (NCT01687387). Eligible pts were: aged 60 to 80 yrs, diagnosed with non-APL AML, in CR1 following standard induction (1 to 2 cycles) and consolidation (1 to 2 cycles) and had: ECOG performance status of 0-1, adequate hematologic, liver and renal function. Pts were randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks (INT) or 1mg/kg q 4 weeks (CONT) according to a minimization algorithm adjusting for center, primary vs. secondary AML, number of consolidation cycles (1 vs. 2) and cytogenetics. Pts were to receive up to 2 yrs of therapy. The primary endpoint was LFS by independent central review. Results Between November 2012 and July 2014, 153 pts were randomized and 152 pts were treated; Pts characteristics are depicted in Table 1. All had received 7+3 induction therapy. Most pts (81%) received 2 cycles of consolidation prior to inclusion. Consolidation chemotherapy consisted of intermediate-dose single agent cytarabine (IDAC) in 53%, and 5+1 in 47% of the pts, according to the recommendations of the ALFA and FILO cooperative groups, respectively. Median time since diagnosis was 4.9 months (mo) [2.8-15.5]. Median time between CR or the last consolidation and randomization were 3.3 [1.1-5.9] and 1.5 mo [0.3-3.5], respectively. The 3 arms were well balanced apart from a slight trend in favor of the placebo arm for lower age, better ECOG, and use of IDAC as consolidation. In March 2015, based upon DSMB recommendation, treatment of pts in CONT was discontinued in light of an excess of early relapses. Mean number of treatment cycles administered was 14.7, 8.8 and 13.8 in the INT, CONT and placebo arms respectively and only 6 pts had one cycle postponed in the lirilumab arms. Major reasons for study discontinuation were relapse (63%) and adverse events (AE) (10%). AE rate was analyzed by taking into account the exposure across pts in each arm. Slightly more AE rate of G1-G2 asthenia, diarrhea and pruritus was observed in CONT arm. Occurrence of hematological disorders did not differ between the 3 arms. 17 pts (11%) experienced second primary malignancies across the 3 arms. PK/PD results were in line with the model predictions: transient full KIR occupancy lasting 7-28 days for the majority of the INT arm pts and permanent full occupancy in the CONT arm. Lirilumab is not significantly immunogenic and does not induce major modifications in peripheral blood NK and T cell subsets. With a median follow-up of 36.6 mo [33.4; 38.2], 108 pts experienced relapses and 2 pts died before relapse. LFS results are presented in Table 2. Conclusions Single agent lirilumab administered for up to 24 cycles was well tolerated. Lirilumab did not result in a statistically significant improvement of LFS in the challenging setting of maintenance in AML in elderly pts. Immune-pharmacological studies will be presented. Potential hypotheses relevant for AML and lirilumab monotherapy (e.g. dosage/schedule optimization, partial desensitization by continuous KIR blockade leading to an impaired immunosurveillance by NK cells) for the non-significant trends will be discussed. Disclosures Recher: Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Pautas: Pfizer: Honoraria. Rousselot: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BMS: Research Funding. Castaigne: Pfizer: Honoraria, Research Funding. Jourdan: NOVARTIS: Consultancy, Honoraria. Gardin: Sunesis: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Delannoy: Innate Pharma: Honoraria. Beautier: Innate Pharma: Employment, Equity Ownership. Paturel: Innate Pharma: Employment, Equity Ownership. Andre: Innate Pharma: Employment, Equity Ownership. Zerbib: Innate Pharma: Employment, Equity Ownership. Dulphy: Celgene: Research Funding; Innate Pharma: Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Olive: Imcheck Therapeutics: Other: Cofunder; GSK: Research Funding; Innate Pharma: Research Funding. Pigneux: Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogaran: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Dombret: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai/Roche: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.889.889

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

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. 2568-2568

Abstract: Introduction: AML with multilineage dysplasia (MLD) are included in the WHO subset of "AML with myelodysplasia-related changes" (AML-MRC), together with AML arising from previous MDS or AML with MDS-related cytogenetic abnormalities. In the WHO classification, MLD is defined by dysplasia in at least 50% of the cells in at least two bone marrow (BM) myeloid cell lines. On the other hand, some genetically defined AML subgroups are specifically associated with morphologic changes, but close correlations do not exist for most of these entities. We searched for correlations between BM dysplasia and molecular aberrations in de novo AML patients included in 2 ALFA clinical trials Methods: BM cytomorphology was retrospectively reassessed in 192 patients with de novo AML (excluding CBF-AML), aged 18 to 70 enrolled in ALFA-0702 (n=123) and ALFA-0701 (n=69) clinical trials in 5 centers. 4 distinct morphologists performed the analysis from BM smears. Dysmegakaryopoiesis (DM), dyserythropoiesis (DE) and dysgranulopoiesis (DG) were quantified (respectively on 30, 200 and 200 cells) using 22 criteria designed by GFHC, which allow better evaluation of cytoplasmic and nuclear dysplasia in all BM lineages. Dysplasia was also evaluated using WHO criteria. NPM1, FLT3, MLL, CEBPA, IDH1, IDH2, WT1, DNMT3A, RUNX1, TET2 and ASXL1 gene mutations and EVI1 gene overexpression were detected by standard methods, as previously published (Renneville et al. Oncotarget 2014). Results: In the 192 patients analyzed, the incidence of molecular abnormalities was: MLL-PTD 5% (8/155), NPM1 31% (52/170), FLT3-TKD 9% (15/171), FLT3-ITD 19% (34/171), CEBPA double mutated (CEBPA-dm)11% (17/152), EVI1 overexpression 11% (17/152), IDH1 R132 9% (14/146), IDH2 R140 6% (10/159), IDH2 R172 2% (2/92), RUNX1 8% (6/67), DNMT3A 26% (11/43), TET2 12% (5/43) and ASXL1 7% (4/62). DG, DE and DM was evaluable in 59%, 83% and 85% of the patients, respectively. WHO-MLD was identified in 43/192 (22%) patients, and was not significantly associated with any genetic marker, even in AML with normal karyotype (Table 1). On the other hand, when using GFHC criteria, we observed in NPM1 mutated patients a higher % of bi-tri or multi nucleated megakaryocytes (25% vs 10%, p=0.03), of cytoplasmic DG (74% vs 58%, p=0.03); and more dysplasia in other cell lines including eosinophils, basophils, mastocytes, monocytes (p=0.008). In CEBPA-dm patients, lower % of global DG (21% vs 54%, p=0.04) was seen. In EVI1 overexpressing patients, we found a higher % of global DM, of micromegacaryocytes and of hypolobulated megacaryocytes (80% vs 31%, p=0.01; 18% vs 2%, p=0.01 and 19% vs 6%, p=0.001 respectively). In DNMT3A mutated patients, we observed a lower % of bi-tri or multi nucleated megakaryocytes (2% vs 28%, p=0.01) and a higher % of nuclear and cytoplasmic DG (21% vs 2%, p=0.005 and 1.2% vs 0%, p=0.03, respectively). In TET2 mutated patients, we observed less defects in nuclear segmentation and a higher % of abnormal chromatin condensation in granulocytes (1% vs 9%, p=0.02 and 6% vs 0%, p=0.008, respectively). Conclusion: Presence of WHO-MLD was not significantly correlated with any genetic subgroup. The 22 BM dysplasia parameters designed by the GFHC were evaluable in a majority of patients, and allowed us to find some specific cytomorphologic features in de novo AML with NPM1, CEBPA-DM, DNMT3A, TET2 mutation, or EVI1 overexpression. Those findings suggest that the definition of MLD may be refined by using more in depth quantification of dysplasia, especially with GFCH parameters. This study will be expanded with the inclusion of whole exome sequencing data (ongoing). Table 1. Correlation between MLD, normal karyotype and molecular abnormalities % AML-MLD % AML-MLD in AML with normal karyotype MLL-PTD 37,5% 29% NPM1 25% 28% FLT3-TKD 27% 33% FLT3-ITD 27% 25% CEBPA-dm 0% 0% IDH1 R132 21% 18% IDH2 R140 10% 0% IDH2 R172 0% 0% RUNX1 40% 40% DNMT3A 0% 0% TET2 0% 0% ASXL1 25% 50% EVI1 24% 0% Disclosures Fenaux: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.2568.2568

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. 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. 124, No. 21 ( 2014-12-06), p. 2327-2327

Abstract: Background: Acute myeloid leukemia (AML) is a heterogeneous disease even within the same genetic subgroup, e.g. within the NPM1 mutated subgroup, some patients have additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent reports have shown that minimal residual disease (MRD) in AML, during or after treatment has prognostic impact. However, the clinical assessment of MRD in AML faces many questions. Firstly, which of the potential molecular and/or cellular markers should be included? Secondly, what type of biological sample should be analyzed? Thirdly, what is the sensitivity threshold to set and what are the relevant time frames for the MRD evaluation. The current technology development next-generation sequencing (NGS), opens new perspectives for monitoring MRD in AML, with the opportunity to expand and multiplex various markers. In this context, we tested the NGS technology for MRD monitoring IDH1/2 and DNMT3A in AML cases with mutated NPM1. We validated our results against MRD evaluated by RTqPCR. Patients and methods: In this study, we included 94 patients (pts) from the ALFA 0701 trial. NPM1 monitoring by RTqPCR was performed as previously described (Lambert et al, Oncotarget july 2014). IDH1/2 and DNMT3A monitoring was done by NGS using the Ion Torrent Proton instrument. In order to obtain very high coverage (approximately 2 Millions reads by sample), 24 samples were analyzed per run. Bioinformatic analysis was performed according to our previous work (Boyer et al, Am JHematol 2013). Results. 94 samples from 31 NPM1 mutated pts were analyzed. (17pts were positive for IDH1/2 and 15 were positive for DNMT3A). Sequencing data showed an excellent depth with a median of 2012459 reads (range 102,657 to 5,160,118 reads) and 966,298 reads (range 565,152 to 2,700,349 reads) for IDH1/2 and DNMT3A, respectively. Unfortunately, despite of this excellent coverage, a median of 520 reads were found positive in the negative controls due to a multi steps cross contaminations (OT2, Clonal amplification, purification). Thus, limiting the sensitivity to 0.07% (0.001-0.097%, p 〈 0.001, Fisher’s exact test) and 0.1% (0.011-0.426%, p 〈 0.0001, Fisher’s exact test) for IDH1/2 and DNMT3A, respectively. The correlation with NPM1 MRD was 78% (r = 0.68183, p 〈 0.0001) and 78.6% (r = 0.55514, p 〈 0.0001) for IDH1/2 and DNMT3A, respectively. For the 17 IDH1/2 positive patients, we found concordant MRD results between IDH1/2 mutation and NPM1 RTqPCR in 13 cases: (4 pos/pos), which was associated to disease relapse, (9 neg/neg), which was associated to maintenance of CR1. For the four remaining patients, we have observed a discrepancy between some NPM1 results and IDH1/2 results. Indeed, these 4 patients presented one or more MRD negative points using the NPM1 marker, while rates of the IDH1/2 marker ranged from 0.1% to 47%. Three of them, have relapsed after 504,395,158 days, and all of them with the same NPM1 mutation detected at diagnosis. The one patient, who has not relapsed, did evolve to a myelodysplastic syndrome which was NPM1 negative. For the 15 DNMT3A positive patients, we found co-occurrence of the NPM1 mutation and IDH1/2 mutations in 9 cases (8 pos/pos), which was associated to disease relapse and we found concordant MRD results between DNMT3A mutation and NPM1 RTqPCR, (1 neg/neg), which was associated to maintenance of CR1. For the six remaining patients, we have observed a discrepancy between NPM1 results and DNMT3A results. Indeed, those 6 patients presented a great majority of negative results using MRD monitoring by NPM1, while rates of MRD by DNMT3A ranged from 5% to 45%. All of these 6 pts are still in first CR after a median follow up of 4 years. Bone marrow and PBMC were analyzed for 3 of them. A positive result was observed in all cell fractions except for the T cells compartment. Conclusion. Monitoring of MRD by NGS mutation detection in two genes IDH1/2 is feasible and valuable, because it enabled us to predict relapse in additional patients, with an area under the curve of 0.7971 (95% CI: 0.6693 - 0.9250), and 100% if we include the patient who evolved to MDS. Furthermore, this category of patients may benefit from new targeted therapies such as inhibitors of mutated IDH proteins. On the contrary, DNMT3A is not a good marker for MRD monitoring, because we detected persistence of a preleukemic clone in 40% of patients remaining in CR, reflecting the molecular heterogeneity clonal hematopoiesis. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.2327.2327

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 7 ( 2011-08-18), p. 1754-1762

Abstract: To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association–9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1+ or CEBPA+ and FLT3-ITD− had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-04-349258

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. 114, No. 22 ( 2009-11-20), p. 1594-1594

Abstract: Abstract 1594 Poster Board I-620 Background Nucleophosmin (NPM1) gene mutations are observed in almost one-third of adult acute myeloid leukemia (AML). If the favorable genotype defined by the presence of NPM1 mutations without fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is known to be associated with favorable outcome in patients with cytogenetically normal (CN) acute myeloid leukemia (AML), impact of these molecular abnormalities are still debated in those with cytogenetically abnormal (CA) AML. Patients and Methods We analyzed the role of these factors in newly diagnosed AML patients homogeneously treated in the Acute Leukemia French Association (ALFA) trials between 1990 and 2006 (ALFA 9000, 9801, 9802). Among 1529 patients (15-70 years of age), 554 patients were screened for NPM1 mutation, FLT3-ITD and have informative karyotype. Mutations screening were centrally performed according to previously described procedures. Karyotype was considered as normal if at least 20 normal marrow metaphases were present without any abnormal marrow metaphases. Favorable core binding factor (CBF) AML (74 patients) were excluded from this analysis. Results Among the 480 remaining patients, 137 (29%; median age 48 years, range 17-68) were NPM1 mutated, 22 of them (16%) having CA-AML. We found no difference between NPM1 mutated CN-AML patients (n=115) and NPM1 mutated non-CBF CA-AML patients (n=22) in term of complete remission rate (88% vs 83%; P= .49), overall survival (OS) (39% vs 38 % at 5 years, P= .85), event-free survival (EFS) (33% vs 25% at 5 years, P= .39). However, in the context of the favorable genotype, EFS was significantly longer in the 79 CN- than in the 16 CA-AML patients (41% vs 19% at 5 years ; P= .04) with a trend to better OS (51% vs 31% at 5 years ; P= .12). No significant differences were observed in patients with NPM1 mutated AML but FLT3-ITD (5-year EFS, 12% vs 40%; 5-year OS, 20% vs 60%; P= .47 and .27, respectively), even if the numbers of patients were here very low (35 CN- vs 5 CA-AML). More importantly, the favorable genotype was predictive of a longer EFS and OS in the 267 patients with CN-AML (5-year EFS, 41% vs 19%; 5-year OS, 51% vs 30%; P= .0001 and .001, respectively), while no differences were observed in the 213 patients with non-CBF CA-AML (5-year EFS, 19% vs 16%; 5-year OS, 31% vs 27%; P= .38 and .36, respectively). Conclusion As shown, patients with the favorable genotype but CA-AML had an outcome relatively similar to those with a non favorable genotype and either CA- or CN-AML. The favorable outcome associated with NPM1 mutation in the absence of FLT3-ITD might thus depend on the presence of a normal karyotype. We thus think that larger studies or overviews are needed to definitely answer this question. Disclosures Dombret: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.1594.1594

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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detail.hit.zdb_id: 80069-7