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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: Bulletin de l'Ecole française d'Extrême-Orient, PERSEE Program, Vol. 63, No. 1 ( 1976), p. 5-58

Type of Medium: Online Resource

ISSN: 0336-1519

URL: Article

DOI: 10.3406/befeo.1976.3886

Language: French

Publisher: PERSEE Program

Publication Date: 1976

detail.hit.zdb_id: 2163625-4

SSG: 0

SSG: 6,24

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 162-162

Abstract: Background: For many years the ALFA Group has used high dose DNR, i.e 80 mg/m2/day for 3d as part of the induction regimen for untreated adult AML pts. As the equivalence of DNR and Ida is not known we conducted a phase III study to compare high dose DNR to Ida. We also tested the effect of IL2 for maintenance. Methods: Newly diagnosed AML, aged 50 to 70 years, were randomized to receive AraC 200 mg/m2/day IV x 7 d with either DNR: 80 mg/m2/d x 3 d (arm 1) or Ida: 12 mg/m2/d x 3 d (arm 2) or x 4 d (arm 3). Pts who failed could receive a salvage course with Mitoxantrone x 2 d and AraC1g/m2 12 hrs x 4d. Response was assessed after induction+/− salvage chemotherapy. CR pts received 2 consolidation courses according to the induction arm with DNR: 80 mg/m2 or Ida:12 mg/m2 for 1 day (first course) or 2 days (2nd course) and AraC:1g/m2/12 hrs x 4 days. Pts in CCR after the two consolidation courses were randomized to receive or not a maintenance immunotherapy with IL2: 5.106/m2 for 5 days monthly for12 months. Results: From 2001 to 2006, 468 pts were included (median age: 60 years). The 3 treatment arms were well matched for pretreatment characteristics. CR was achieved in 360/468 pts (77%): 109 (70%) pts arm 1, 129 (83%) arm 2, 122 (78%) arm 3 (p=0.02).70 pts, (45%) pts in the DNR arm reached CR after 1 course vs 97 (62%) and 90 (57%) in Ida arms (p= 0.006). Pts in Ida arms experienced more grade 3 or 4 mucositis (p=0.004) but no differences were observed between the 3 arms for duration of hospitalization, time to PMN or plts recovery, incidence of grade 3 or 4 infectious episodes and treatment related mortality. 3 year cumulative incidence of relapse was 69%, 63%, 62% resp in arms 1,2,3 (p=NS). 3 year EFS was 19%, 30%, 26% resp (p=0.06 for arm 1 vs arms 2 and 3). 3 year OS was 31%, 40% 41% resp in arms 1,2,3 (p=NS). Age ( & lt; or & gt;60 years), sex, initial WBC counts, initial LDH (nl or & gt;nl), DNR or Ida arms, need for a salvage course were not predictive for relapse, while 2yCIR was 43%, 64%, 77% among respectively fav, intermediate and unfav cytogenetic risk groups resp (p=0.0046). Of the 219 pts alive in CR after consolidations, 161 (73%) were randomized for maintenance. Only 22 of the 77 pts randomized for IL2 completed the 1 year treatment. 32 and 23 pts stopped IL2 resp because of relapse or intolerance. There were no differences in relapse or OS in both maintenance arms. Conclusion: Ida treatment even when compared to high doses of DNR yields higher CR rate and more CR after one course. This effect translated in slightly better EFS but not better CIR or OS. IL2 maintenance treatment at least as scheduled in this trial was difficult to apply and showed no impact on disease course.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.162.162

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4007-4007

Abstract: Background: High-risk (HR) AML including secondary AML (sAML) or therapy-related (tAML) are associated with significantly lower complete remission (CR) rates and poor outcome, after upfront "3+7" and post-remission chemotherapy. No standard intensive treatment approach for relapsed/refractory AML is well established, even more so, in older patients, but "bridging" such patients in CR to allogeneic stem-cell transplantation (HSCT), whenever feasible, remain the only curative strategy, as in younger patients. Addition of cladribine, a purine analog, to cytarabine is an available option. Significant clinical activity of CLAG (-M) regimens is now well established, with a response rate (RR) of 60% in relapsed/refractory AML or AML patients who failed hypomethylating agents. A prospective frontline study of an intensified CLAG-M regimen has recently confirmed its association to a high response rate, that may particularly benefit HR-AML patients, as a bridge to HSCT. As other reports in the literature remain sparse, we report here our current experience with CLAG-M in relapsed/refractory and sAML patients. Methods: From January 2015 to July 2018, 20 consecutive patients with HR-AML, were treated in our center, with one course of CLAG-M (cladribine 5 mg/m2 /day (days 2-6), cytarabine 2g/m2/day (days 2-6) and reduced to 1g/m2/day for patients 65y+, filgrastim 300mcg/daily (days 1-6), and mitoxantrone 10mg/m2/day (days 2-4)). If eligible for HSCT, a second CLAG course was to be administered to patients in CR. Extended myeloid mutation analysis was performed, using a 37-gene NGS panel. Such patients were classified according to Lindsley et al.,Blood 2015. Results: Median age was 63.5 years (33-79) with a 3:1 M/F ratio. Four sAML patients and 4 tAML patients were treated upfront (5 CR, 1 early death (ED) and 2 treatment failures). ELN cytogenetics was adverse (n=5), intermediate (n=1) or failed (n=4). Twelve patients were all treated after frontline 7+3 and intensive consolidation courses (n=10) or azacytidine (n=2). Three patients were refractory to prior intensive chemotherapy or AZA and 9 were in first or subsequent relapse, at time of CLAG-M administration. Median time from first treatment for MDS/AML to CLAG-M onset was 17 mos (3-29). Initial/relapse ELN cytogenetics was adverse (n=5), intermediate (n=5) and failed (n=2). Of these 12 patients, 7 obtained a response (6 CR, one CRi), 3 failed to obtain a response and 2 early died from sepsis. Seventeen patients could be classified, according to Lindsley et al. The 3 patients with missing NGS data, all had adverse ELN cytogenetics (inv3q/MECOM1, MLLr by FISH analysis or monosomy 7, associated with an IDH2 mutation). After one course, 5/7 patients, classified as secondary AML, obtained a CR, including one CRi, 3/4 patients classified as pan AML obtained a CR, while only 2/6 patients with mutated TP53 alleles obtained a CR (3 failed to respond). Overall, 12 of the 20 patients obtained a complete response (11 CR and 1 CRi), despite adverse genetical characteristics and 12 of them being administered CLAG-M, during the late evolution of their disease. Three patients early died due to undocumented pneumonitis (n=2) or bacterial sepsis (n=1). Otherwise, observed treatment toxicities were mild, with no unusual infections seen after CLAG-M. Median duration of neutropenia ( 〈 0.5 G/l) and thrombocytopenia ( 〈 100 G/l) was 28 (12-47) and 30 (23-40) days, respectively. Seven patients in CR received a second CLAG course before HSCT, when 3 patients, aged more than 70 years, only less intensive courses. One CR patient did not received consolidation due to severe sepsis, as also did the only patient with CRi due to persisting cytopenias. Both patients underwent HSCT. Fifteen patients were deemed eligible at entry for HSCT, based on age and performance status. Of those, 8 achieved a CR/CRi and all of them proceeded to HSCT. Four such patients are currently alive (2 mo, 2.6 y, 3y, 3.4y), 2 patients died from early relapse (4 and 6 mos) and 2 patients from HSCT toxicity. Conclusions: In this real-life small study of HR-AML patients, predominantly older than 60 years of age, CLAG-M was also used at first or subsequent relapse post-intensive therapy. Despite very unfavorable characteristics, 60 % of them obtained a complete response and 50% of those initially eligible were effectively "bridged "to HSCT, without unusually deleterious outcomes observed in this small cohort. Disclosures Peffault De Latour: Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Braun:CELLIPSE: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-117237

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. 122, No. 21 ( 2013-11-15), p. 658-658

Abstract: Although anemia of LR MDS initially responds to erythroid stimulating agents (ESA) in 40-50% of patients, response is generally transient. AZA may lead to RBC transfusion independence (RBC-TI) in 30-40% of LR-MDS patients but it has not been studied prospectively in those resistant to ESA. While prognostic factors of response and survival to AZA have been largely analysed in high risk MDS, including by our group (Itzykson, Blood, 2011), they remain uncertain in LR-MDS, especially regarding new genetic factors. We previously reported (J Clin Oncol 30, 2012 # 6523) in a randomized phase II trial comparing AZA and AZA+EPO in 93 LR-MDS that were RBC-TD and resistant to ESA, a similar erythroid response rate in the 2 treatment arms (NCT01015352). Here, we report prognostic factors of response and overall survival in this trial, including genetic markers (SNP array-based karyotype and somatic mutations). Methods Patients included in the trial received AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) or with added EPO 60000U/week (AZA+EPO arm). Erythroid response was evaluated after 4 and 6 cycles of AZA, according to the IWG 2000 criteria. Responders were then eligible for 12 AZA+/-EPO maintenance cycles. Affymetrix SNP array 6.0 (SNPa) analysis was performed at baseline on marrow mononuclear cells, and mutations of SF3B1, TET2, DNMT3A, ASXL1, JAK2 and 19 other genes were screened by next generation sequencing and validated by Sanger sequencing. The following factors were analysed for their prognostic value on erythroid response (IWG 2000) and survival: age, gender, IPSS, IPSS cytogenetics, WHO diagnosis, time since MDS diagnosis, SNPa karyotype, SF3B1, TET2, DNMT3A, ASXL1 and JAK2 mutations. Results In the 93 patients, M/F was 65/28; median age 72 y (IQR: 65-78); WHO diagnosis: RA 5.3%, RARS 40.9%, RCMD 15.1%, RCMD-RS 17.2%, RAEB-1 12.9%, CMML 7.5%, MDS-U 1%. Median MDS duration prior to inclusion was 37.2 months. IPSS was low in 35 and int-1 in 57 patients (NA in 1). IPSS cytogenetics was fav in 65, int in 9, defav in 2 patients, and failed or not done at study entry in 17 (but cytogenetics at MDS diagnosis was available in 16 of them). An abnormal SNPa karyotype was present in 33/79 patients analysed, including 9 with normal conventional cytogenetics. SF3B1, TET2, DNMT3A, ASXL1 and JAK2 mutations were detected in 59/86, 29/87, 12/87, 5/89 and 3/87 patients. Of the 19 other genes analysed, 12 showed no mutation and 7 (UA2F1, CBL, EZH2, RUNX1, ETV6, KIT, IDH2) were mutated in ≤3 patients and were not further considered in this analysis. In ITT analysis (N=93), erythroid response was 34% after 4 courses (37.5 % vs. 31% in the AZA and AZA+EPO arms, respectively, p=0.82) and 30% after 6 courses (35% vs. 24%, p=1.00). In univariate analysis, none of the factors listed above, including genetic markers, significantly predicted treatment response after 4 or 6 courses, while a trend was observed for a higher response rate after 6 cycles for SF3B1 mutated versus wt. patients (35.6 vs. 14.8 % respectively, P=0.07). Median follow-up of the 93 patients was 30 months (IQR: 23-34). Five patients developed AML (1 in AZA arm and 4 in AZA+EPO arm, P=0.19), all 5 in non-responders after 6 cycles. Median OS was 42.2 months and 2.5 years-OS 79.2% (95%CI: 71.2-88.1), with no difference between randomization arms (P=0.69). In univariate analysis, a shorter time since MDS diagnosis (HR=0.97, 95%CI: 0.95-0.99,P=0.011), IPSS int-1 (HR=2.83, 95%CI: 1.05-7.63, P=0.04), an abnormal SNPa karyotype (HR=3.01, 95%CI: 1.26-7.22, P=0.013) and presence of ASXL1 mutation (HR=5.08, 95%CI: 1.48-17.48, P=0.010) were associated with worse survival. In multivariate analysis, however, only time since MDS diagnosis (HR=0.97, 95%CI: 0.95-0.99) and abnormal SNPa karyotype (HR=2.92, 95%CI: 1.07-8.01) remained of prognostic value. Conclusions In this prospective AZA trial in LR-MDS resistant to ESA, no significant prognostic factor for response to AZA+/- EPO was identified, but a trend for better response (p=0.07) was seen in SF3B1 mutated patients, i.e 2/3 of patients. Among mutations analysed, only ASXL1 mutation predicted survival in univariate analysis, while abnormal SNPa karyotype predicted survival both in univariate and multivariate analysis (together with MDS duration). Thus, SNP array-based karyotyping and ASXL1 gene mutation analysis may become important tools to predict the long-term outcome of ESA resistant LR-MDS treated by AZA Disclosures: Guerci-Bresler: Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Fenaux:Celgene, Inc: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gardin:Celgene, inc: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.658.658

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. 116, No. 21 ( 2010-11-19), p. 3513-3513

Abstract: Abstract 3513 Purpose: Based on donor versus no-donor studies, allogeneic stem cell transplantation (SCT) is the best treatment option for younger patients with intermediate- or adverse-risk AML in first CR (Cornelissen et al. Blood 2007; Koreth et al. JAMA 2009). However, in these intent-to-treat studies, the benefit associated with SCT seems often small in the adverse-risk subgroup, probably due to a higher incidence of early relapse. In addition, the definition of the donor group has evolved with the increasing use of alternative SC sources. To assess the role of current SCT procedures in adverse-risk patients specifically, we thus performed the present real-life transplant versus no-transplant analysis. Patients and Methods: A total of 205 adults aged 50 years or less with adverse-risk AML in first CR (CR1) were included. All have reached CR1 after induction therapy within the ALFA-9000 (N=69; period 1990–1996) or ALFA-9802 (N=136; period 1999–2006) trial. Adverse-risk AML was defined as: 1) unfavorable cytogenetics, including 3q26 or 11q23 anomalies, del(7q)/-7, del(5q)/-5, and complex karyotypes (N=106); 2) initial WBC 〉 100.109/L (N=72); 3) late CR1 achievement (N=47); and more recently 4) FLT3-ITD, after protocol amendment in 2002 (N=35). Patients with CBF-AML were excluded. Among these 205 eligible patients (median age, 38y), 102 (50%) received SCT, including 74 patients in CR1 (36%). In CR1 patients, the median time between CR and SCT (60 sibling and 14 unrelated donors, including 4 cord blood; 65 myeloablative and 9 reduced intensity [RIC] conditioning) was 88 days (5%-95% percentiles, 24–245). In patients allografted after relapse, the median time between relapse and SCT was 109 days (5%-95% percentiles, 8–205). Outcomes of transplanted versus non-transplanted patients were compared using Mantel-Byar estimates. The median follow-up was 7 years. Results: According to SCT in CR1, both transplant and no-transplant groups were comparable in terms of age, WBC, cytogenetics, and time to CR. Transplant rate in CR1 was higher in the latter 9802 trial (42% versus 25%, P=0.02), due to the increasing use of unrelated donors over time (24% versus 0%, P=0.03). Overall, Mantel-Byar estimates revealed a better outcome of patients transplanted in CR1 compared to those not transplanted in CR1. At 5 years, estimates were 43% (95%CI, 31–54) versus 20% (95%CI, 13–28) (Figure 1; P=0.05) and 41% (95%CI, 29–53) versus 26% (95%CI, 19–34) (P=0.17) for DFS and OS from CR in the transplant and no-transplant groups, respectively. Notably, SCT was associated with an impressive decrease of relapses (5-year cumulative incidence, 30% [95%CI, 21–43] versus 77% [95%CI, 69–84] ; P 〈 0.0001), attesting that a strong and long-lasting anti-AML effect can be achieved with SCT even in these patients at very high risk of relapse. Similar results were observed in various adverse-risk subsets (unfavorable, complex, or monosomal karyotypes; high WBC). In patients not transplanted in CR1, almost 20% of relapses occurred within the first 3-month period (i.e. the median time to SCT in transplanted patients). In patients relapsing without having been transplanted in CR1, SCT after relapse was, however, not able to prolong OS which was as poor as in patients not transplanted after relapse (10% at 5 years). Conclusion: Even if SCT results remain unsatisfactory, this real-life study confirms its superiority over chemotherapy in patients with adverse-risk AML in CR1. With a very high short-term relapse incidence and evidence of anti-AML allogeneic effect, the study also provides a strong rationale to propose upfront early sequential regimens to these patients, combining innovative chemotherapy and RIC-SCT (Schmid et al. Blood 2006). This option will be prospectively evaluated in the next younger AML French ALFA-GOELAMS Intergroup trial. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3513.3513

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: British Journal of Haematology, Wiley, Vol. 111, No. 3 ( 2000-12), p. 801-806

Type of Medium: Online Resource

ISSN: 0007-1048

URL: Article

DOI: 10.1111/j.1365-2141.2000.02442.x

Language: English

Publisher: Wiley

Publication Date: 2000

detail.hit.zdb_id: 1475751-5

In: Leukemia Research, Elsevier BV, Vol. 36, No. 9 ( 2012-9), p. 1112-1118

Type of Medium: Online Resource

ISSN: 0145-2126

URL: Article

DOI: 10.1016/j.leukres.2012.04.020

Language: English

Publisher: Elsevier BV

Publication Date: 2012

detail.hit.zdb_id: 2008028-1