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In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 7 ( 2020-07), p. 1730-1740

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-019-0685-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 147-147

Abstract: Introduction: In a recent French FRALLE versus LALA comparison, we have demonstrated a large benefit in outcome when adolescents and young adults were treated in a pediatric rather than an adult ALL protocol (Boissel JCO 2003). Similar provocative results have been observed in three other pediatric versus adult ALL studies (Stock ASH 2000, de Bont Leukemia 2004, Testi ASH 2004). One explanation may be the larger amounts of steroids, vincristine (VCR), and L-asparaginase (L-aspa) administered in pediatric patients. The GRAALL-2003 study was thus designed to offer a pediatric approach in adults with Ph-negative ALL until 60 years of age. Methods: Treatment included a 5-drug induction, high dose-intensity consolidation blocks, delayed intensification, and 2-year maintenance. The comparison with the former LALA-94 protocol showed a 8.6-fold, 3.7-fold, and 16-fold increase in cumulative doses of prednisone, VCR, and L-aspa, respectively. One difference with childhood ALL therapy remained indication of allogeneic SCT in first CR which was offered to all patients with high-risk factor and a donor. In addition, induction was reinforced with a hyper-cyclophosphamide sequence (HyperC) in case of poor early response (cortico- and/or chemoresistant ALL). In the present report, 212 GRAALL-2003 patients with Philadelphia-negative ALL aged 15–55 years with a median follow-up of 18 months were compared to 712 patients previously treated in the LALA-94 trial. Results: Cohorts were comparable in terms of prognostic factors. CR rate was significantly higher in GRAALL patients (93 vs 88%, P=0.02) due to a reduction in resistant disease (0.5 vs 8%, P 〈 0.001) with comparable induction death (6 vs 5%, P=0.37) rate. When compared to the LALA-94 study, 2-year EFS and overall survival were markedly improved (56 vs 41% and 66 vs 54%; P=0.0002 and 0.02, respectively). Similar differences were observed after censoring SCT patients at transplant time, underlining the role played by chemotherapy modification. Because of a worse tolerance to induction and post-remission therapy, the benefit associated with the GRAALL approach decreased with advanced age, becoming not statistically significant over 40 years of age. Finally, outcome improvement was higher in T- than in B-lineage ALL (2-year overall survival, 75 vs 51% and 61 vs 56%; P=0.016 and 0.25, respectively). Among patients with T-ALL, poor early responders (allocated to HyperC induction) tended to have a better EFS than good early responders, suggesting a major role of HyperC in this ALL subset. Conclusion: In conclusion, a pediatric approach benefits to younger adults with ALL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.147.147

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 895-895

Abstract: Background: In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC 〉 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation. Methods: Between 2006 and 2015, newly diagnosed APL pts 〈 70 years with WBC 〉 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement. Results: 211 pts 〈 70 years with WBC 〉 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS. 5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC 〉 1 G/L after consolidation 2 was 22, 25 and 19 days (p 〈 0.0001), and median time to platelets 〉 50G/l was 24, 26 and 20 days (p 〈 0.0001). Similarly, median duration of hospitalization after the first and the second consolidation courses were 33, 34, 29 d (p 〈 0.0001) and 31, 32, 28 d (p=0.0005), respectively. Conclusion: Very high CR rates and very few relapses are now obtained in high risk APL on a large multicenter basis using classical ATRA and CT (including AraC) for induction and consolidation, and maintenance treatment, but at the expense of 5 to 7% deaths in CR. Addition of ATO to this regimen did not further reduce relapses, and added some myelosuppression if CT contained AraC. However, if ATO was added and AraC omitted from consolidation cycles, relapses were not increased, while myelosuppression and deaths in CR were reduced. ATO therefore appears useful in high risk APL. We are currently comparing, in the international APOLLO trial, the "classical" ATRA-CT approach and a prolonged ATO-ATRA regimen with only 2 days of Ida during induction treatment, hoping to further reduce myelosuppression and possibly relapses. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.895.895

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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. 2088-2088

Abstract: Abstract 2088 Poster Board II-65 Background: APL is highly curable with the combination of ATRA and anthracycline based chemotherapy (CT), but very long term results of this treatment remain unpublished. We present here the very long term results of APL93, that included newly diagnosed patients ( pts) between 1993 and 1998, with a 10 year median follow-up, particularly focusing on late events. Methods: For induction treatment. Pts aged ≤65 years with WBC 〈 5,000/μL were randomized between ATRA 45 mg/m2/d followed by CT (DNR 60 mg/m2/d × 3 d + AraC 200 mg/m2/d for 7 d :ATRA→CT group) or ATRA plus CT (ATRA+CT), where the same CT was started on day 3 of ATRA treatment. After CR achievement, they received 2 consolidation courses of DNR and AraC (the first identical to the induction course, the second with DNR 45 mg/m2/d for 3 days and 1g/m2/12h AraC for 4 days). Pts with baseline WBC 〉 5,000/μL (irrespective of their age) and pts aged 66-75 years with WBC count ≤ 5,000/μL were not randomized but received ATRA with addition of CT on day 1 of ATRA treatment (high WBC group) and the same schedule as in the ATRA→CT group (elderly group), respectively. The elderly group received only the first consolidation course. For maintenance, pts were randomized to receive or not (2×2 analysis) intermittent ATRA (45 mg/m2 /d, 15 days every 3 months) and to receive or not continuous CT with 6MP (90 mg/m 2 /d, orally) and MTX (15 mg/m 2 /wk, orally) scheduled for 2 years. Interim results of this trial have been published (Blood 1999, vol 94, 1192-200). Results: In the 576 APL included, the CR rate was 87.3% and 90.7% in the elderly and the high WBC groups, respectively (resp), and ,in randomized pts, was 92.6% and 96.2% in the ATRA→CT and ATRA+CT groups , resp(p= 0.19). With a median follow-up of 121 months, 142 (26.6%) pts had relapsed, 59 (11%) had died in CR and 329 (61.7%) remained in first CR. 18 (12.7% of the relapses, 3.3% of the patients in CR), 9 and 3 relapses occurred after 4, 6 and 8 years, resp. Based on initial stratification, the 10-year cumulative incidence of relapse (CIR) was 16.5% in pts 〈 65 years with WBC 〈 5,000/μl, 37.9% in the high WBC group and 9.3% in the elderly group (p 〈 0.0001). 10-year OS was 77% in the whole population, and 78.6%, 63.1% and 58.1% in randomized, high WBC and elderly groups, resp (p 〈 0.0001). In pts 〈 65 years with WBC 〈 5,000/μl ( ie randomized at diagnosis), , 10-year EFS (primary end point of the 1stRandomization) was 64.4% in the ATRA→CT group and 76.3% in the ATRA+CT group (p=0.019), 10-year CIR was 21.6% in the ATRA→CT group and 13.2% in the ATRA+CT group (p=0.087); and 10-year OS was 81.8% vs. 85.0% in the ATRA→CT and ATRA+CT groups, respectively (p=0.23). Regarding maintenance, 10-year CIR (Primary endpoint of the 2ndrandomization) was 43.2%, 33%, 23.4% and 13.4%, after no maintenance, maintenance with ATRA alone, CT alone and both, resp (p 〈 0.0001). In pts with WBC 〉 5,000/μl, the 10-year CIR was 68.4%, 53.1%, 32.8% and 20.6% with no maintenance, ATRA alone, CT alone and both, resp (p 〈 0.0001). In pts with WBC 〈 5000/μL, the 10-year CIR was 29.2%, 22.9%, 21.0% and 11.5% with no maintenance, ATRA alone, CT alone and both, respectively (p =0.069). 41/322 pts received maintenance 〈 1 yr due to side effects or to patient or physician's decision. Hazard of relapse was significantly increased in pts who received maintenance 〈 1 yr vs 〉 1 yr (HR= 0.16 p 〈 0.0001). 59 patients (11%) died in first CR ( 10-year cum incidence (CI) of 5.7%, 15.4% and 21.7% in patients aged 〈 55, 55-65 , 〉 65 y, resp). Sepsis secondary to neutropenia (occurring during consolidation but also in 6 cases, during maintenance) and solid tumors accounted for 39% and 15% of death in CR, respectively. CI of secondary tumors and MDS was 1.4% and 0.2% at 5 years, 2.7% and 1.1% at 10 years. Conclusion: Our results with a median follow-up of 10 years, confirm that the combination of ATRA and chemotherapy can cure 〉 75% of APL and show the long term usefulness of sufficiently prolonged maintenance treatment, particularly in pts with initial WBC counts 〉 5000/μl and, in pts with WBC counts 〈 5000/ul, the probable benefit of early addition of CT to ATRA. Very few long-term complications were seen. However, reduction of the incidence of deaths in CR in this highly curative disease is mandatory and requires reduction in the use of myelosuppressive drugs. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2088.2088

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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. 3710-3710

Abstract: Purpose: Best supportive care is generally offered to older patients presenting with refractory/relapsed acute lymphoblastic leukemia (ALL). There is clearly a need for new therapeutic approaches in these older patients for whom aggressive chemotherapies cannot be administered. Materials and Methods: The present study evaluated the addition of epratuzumab (hLL2), a humanized monoclonal therapeutic antibody against CD22, to the combination of vincristine and dexamethasone in older patients ( 〉 55 years) with relapsed/refractory CD22+ B-ALL. The salvage regimen consisted of epratuzumab 360 mg/m²/d iv days 1, 8, 15, and 22, vincristine 2 mg iv days 1, 8, 15 and 22, and dexamethasone 40 mg/d po days 1, 8, 15, and 22. Morphologic and phenotypic minimal residual disease (MRD) responses were determined between 4 and 6 weeks from day 1. Results: Between November 2010 and December 2013, 26 patients from six French centers were enrolled in the study. One case was excluded because of progression before receiving the treatment, while 2 younger patients were inappropriately included (49-year old female in fourth relapse and 32-year old female with refractory second relapse). Among the 25 patients considered for analyses, there were 13 males and the median age was 65 years. Eighteen, 4, 1, and 1 patients were in first, second, third, and fourth relapse, respectively, and one case had refractory B-ALL. Median percentage of blasts in bone marrow was 72%. Karyotypes were as follow: normal n=8; Ph+ n=6, complex n=1, MLL rearrangement n=1, hyperdiploidy n=2, hypodiploidy n=2, 17p duplication n=1, del9p n=1, t(1;19) n=1, t(13;14) n=1, 14 abnormality n=1. Median interval between diagnosis and salvage regimen was 16 months. Three patients were previously allotransplanted. Two patients died of progression during treatment. Salvage regimen was overall well tolerated, since the large majority of grade 3/4 toxicities were expected pancytopenia. One grade 3 toxicity was related to the first epratuzumab infusion, but the patient received the three other infusions without events. One grade 3 renal injury and one grade 4 hypertriglyceridemia of unclear etiology also were documented. The overall response rate was 40% (n=10), including 4 complete responses (CR) and 1 CR with incomplete platelet recovery (CRp) (20%), and 5 partial responses (PR) (20%). Two patients in CR/CRp were documented with negative MRD. All patients in CR/CRp and 1 patient in PR received a second cycle as consolidation. All patients died of disease progression, except two non-responder cases. Median OS was 4 months (range: 0.5-43). Median DFS for those achieving CR/CRp was 4 months (range: 1-8). Conclusion: Non-intensive chemoimmunotherapy combining vincristine/dexamethasone/epratuzumab provides encouraging results in this very high-risk, refractory/relapsed, older population. These results pave the way for integrating epratuzumab within first-line chemotherapies in older CD22+ B-ALL patients. This trial is registered at http://clinicaltrials.gov/ct no.NCT01219816. Disclosures Leguay: Gilead Sciences: Research Funding. Goldenberg:immunomedics: Employment. Wegener:immunomedics: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3710.3710

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. 114, No. 22 ( 2009-11-20), p. 845-845

Abstract: Abstract 845 Background: ATRA combined to anthracycline-based chemotherapy (CT) for induction and consolidation followed by prolonged maintenance is a standard treatment of newly diagnosed APL, but the outcome and prognostic factors in the elderly are less well established than in younger patients (pts). Methods: We performed a joint analysis of elderly pts included in two subsequent trials of the PETHEMA group (LPA96 and LPA99) and and on the French -Belgian-Swiss APL group (APL93 and APL2000). In the PETHEMA trials, pts received induction therapy with ATRA and idarubicin (Ida 12 mg/m2/d, d2,4,6,8), consolidation with 3 anthracycline monochemotherapy courses (2 with Ida and 1 with mitoxantrone, with ATRA and higher idarubicin dose for Sanz's int and high risk pts in LPA99 trial), and 2-year maintenance with intermittent ATRA and continuous low-dose CT (6MP + MTX). In APL 93 and 2000 trials: pts received induction therapy with ATRA and DNR (60mg/m2/d ×3d)+AraC, (200 mg/m2/d×7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d × 3) + AraC (1-2 g/m2/12h × 8) course (omitted in pts 〉 65y) and the same maintenance as in PETHEMA trials. Median follow up was 75 and 42 months in PETHEMA and APL trials, respectively. Results: 1575 consecutive newly diagnosed APL pts were enrolled in the 4 trials, including 1288 (81%), 105 (6.6%), 91 (5.7%) and 91 (5.7%) aged 〈 60, 60-65, 65-70, and 〉 70, respectively (ie 287 pts (18%) older than 60). CR rates in these age groups were 94.6%, 84.8%, 81.8% and 78.4% (p=0.0002). All failures were due to early death, except one due to resistant leukemia, in a younger adult. The 5-year cumulative incidence of relapse was 16.5%, 19.1% ,11.9% and 13.5% in pts 〈 60, 60-65, 65-70 and 〉 70, respectively (p= 0.63). The 5-year OS in these age groups was 85.8%, 68.7%, 63.8% and 56.4% (p 〈 0.0001). The 5-year rate of death in CR , mainly resulting from myelosuppression during post induction treatment, increased with age, from 3.1%, 11.8%, 14.6% up to 17.9% in patients 〈 60, 60-65, 65-70 and 〉 70 years, respectively (p 〈 0.0001). By multivariate analysis stratified on the trial (APL and LPA), better OS was associated with age 〈 60 (HR 2.645, p 〈 0.0001), female gender (HR 0.77, p=0.05), lower WBC (HR 1.007, p 〈 0.0001) and higher platelets (HR 0.996, p=0.03). In pts 〉 60 yrs, by multivariate analysis, early death was associated with increased WBC (p=0.046), and increased creatinine level (p=0.002). Higher CIR was associated with increased WBC (p=0.002) . In patients older than 60 years, age had no significant impact on CR rate and survival. Finally, no significant differences in outcome were seen between French Belgian Swiss and PETHEMA trials. Conclusion: In pts older than 60, classical APL treatment with ATRA combined to anthracycline based CT followed by prolonged maintenance gives no initial leukemic resistance and similar relapse rate as in younger pts, but significantly lower OS due to a higher incidence of early deaths and of deaths in CR compared with younger pts. Higher WBC counts are associated with an increased incidence of both early deaths and deaths in CR. Improvement in prognosis, therefore, requires better supportive care during induction treatment, while reduction of the amount of myelosuppressive drugs during post induction treatment may be required to reduce deaths in CR. Disclosures: Fenaux: CELGENE: Research Funding; AMGEN: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.845.845

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6114-6116

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-166035

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

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. 13-13

Abstract: Abstract 13 Background: The combination of ATRA and anthracycline based chemotherapy (CT) is the reference induction and consolidation treatment of newly diagnosed APL. Whereas in high risk pts (ie with baseline WBC 〉 10G/L), AraC is often considered useful in combination with an anthracycline to prevent relapse, CT with idarubicin alone appears sufficient to yield very low relapse rates in standard risk APL (with WBC 〈 10G/L) (Ades, Blood 2008, 111:1078-84). On the other hand our APL2000 trial, where standard risk pts were randomized between ATRA with DNR+AraC and ATRA with DNR without AraC, was prematurely terminated after the first interim analysis due to significantly more relapses and shorter survival in the arm without AraC (JCO 2006, 24:5703-10). We reevaluated those results, 6 years after the last patient inclusion. Methods In APL 2000 trial newly diagnosed APL patients 〈 60 years with WBC 〈 10G/L were randomized between the AraC+ group: induction with ATRA 45mg/m2/d until CR and DNR 60 mg/m2/d x3 + AraC 200mg/m2/d x7 started on day 3; first consolidation with the same CT course, second consolidation with DNR 45 mg/m2/d x3d and AraC 1g/m2/12h x4d; maintenance during two years with intermittent ATRA (15 d/ 3 months) and continuous 6 MP + MTX, and the AraC- group: same treatment, but without AraC. Pts 〈 60 years with WBC 〉 10 G/l (high WBC Group) were not randomized but received the AraC+ group treatment, but with higher AraC dose during the second consolidation (2 g/m2/12 hx 5 days). The current analysis was made at the reference date of 1 January 2010, 72 months after inclusion of the last pt. Results: Overall, 340 pts entered APL 2000 trial between July 2000 and Feb, 2004 (pts included in APL2000 trial after termination of inclusion in the AraC- group, until 2006 are not analyzed here). The AraC+ and AraC- groups (95 and 101 pts, resp) were well balanced for all pretreatment characteristics except WBC count that was higher in the AraC+ arm (mean 2.8 vs. 2.4 Giga/L). In the AraC+, group, 94 pts (99 %) achieved CR and one had early death (ED), as compared to 95 (94 %) CR in the AraC- group (p= 0.12), while there were 1 vs. 4 early deaths (ED), and 0 vs. 2 resistant leukemias in the two arms. The 5-year cumulative incidence of relapse, EFS and survival were 13.4 % vs. 29.0% (p = 0.013), 82.2% vs. 64.8% (p = 0.01), and 92.9% vs. 83.3% (p = 0.07) in the AraC + and AraC- group, respectively. Of the 23 relapses in the AraC- group, 20 were Hematological Relapses and 3 were Molecular Relapses, as compared to 10 and 2, respectively, for the 12 relapses in the AraC+ group. In the high WBC group (where there was no randomization and all pts received AraC), the CR rate, 5-year CIR, 5-year EFS and 5-year survival were 97%, 7.5%, 82.5%, and 89.8%, ie an outcome that appeared slightly superior to that of standard risk pts treated without AraC. Conclusion: With longer follow up, our findings suggest that, in standard risk APL(WBC 〈 10G/l), avoiding AraC for chemotherapy may lead to an increased risk of relapse when the anthracycline used is DNR. Our results caution against the use, in standard risk APL, of very effective treatment regimens without AraC like the PETHEMA 99 trial (Sanz, Blood 112:3130-34), but where idarubicin would be replaced by DNR. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.13.13

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 5, No. 1 ( 2021-01-12), p. 176-184

Abstract: CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD & lt;10−3 was achieved in 57% of complete response (CR)/CR with incomplete hematological recovery (CRi) patients. Only the presence of mutated TP53 (P = .02) or PTPN11 (P = .004) predicted lower response in multivariate analysis. Interestingly, high-risk molecular prognosis subgroups defined by 2017 European LeukemiaNet risk stratification, including ASXL1 and RUNX1 mutations, were not associated with a significantly lower response rate using CPX-351. With a median follow-up of 8.6 months, median overall survival (OS) was 16.1 months. Thirty-six patients underwent allogeneic stem cell transplantation with a significantly longer median OS compared with nontransplanted patients (P & lt; .001). In multivariate analyses, only spliceosome mutations were associated with better OS (P = .04). In comparison with intensive chemotherapy, there was no difference in OS for patients & lt;60 years. These data confirm the efficacy and safety of CPX-351 in high-risk AML (t-AML and MRC-AML) in a real-life setting. CPX-351 is a treatment of choice for patients aged ≥60 years.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2020003159

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 31-31

Abstract: Background. Tyrosine kinase inhibitors (TKI) are standard front-line therapy for patients with BCR-ABL1/Philadelphia positive ALL (Ph+ ALL), but the relative merits of available TKIs remain uncertain. Nilotinib is a potent inhibitor of BCR-ABL1 with broader activity against ABL kinase domain mutations than imatinib and greater selectivity than dasatinib or ponatinib. As there is a paucity of data on nilotinib as first-line therapy for Ph+ ALL, the EWALL (European Working Group for Adult ALL) conducted an international clinical trial to evaluate efficacy and safety of the combination of nilotinib with low intensity chemotherapy. Patients and Methods. After a prephase with dexamethasone (DEX) and cyclophosphamide, nilotinib (400 mg BID) was given concurrently with the same chemotherapy backbone employed in the EWALL-PH01 assessing the combination with dasatinib (Rousselot et al, Blood 2016;128:774-82). Induction consisted of nilotinib combined with weekly vincristine (VCR, 1mg iv) and oral dexamethasone 40mg 2 days (20 mg over 70y). Nilotinib was continued throughout six consolidation cycles, followed by 24 months maintenance therapy with nilotinib, 6-MP, MTX and DEX/VCR boosts. Stem cell transplantation (SCT) was permitted as considered appropriate. BCR-ABL1 RTQ-PCR and kinase domain resistance mutations were centrally monitored. Primary endpoint was event-free survival (EFS) at 12 months, secondary endpoints included rates of CR, major and complete molecular response, relapse free survival (RFS), EFS and overall survival (OS). Results. 72/79 enrolled pts. were evaluable for response, 3 withdrew consent, 4 did not meet eligibility criteria. Median age was 65.5 (55-85) years, male/female ratio 0.85, ECOG status 0 or 1 in 89% of pts., median CIRS comorbidity score 5(0-19). Baseline vascular risk factors including high blood pressure (grade ≥2) were present in 36% of pts.. Sixty-eight of 72 pts. (94.4%) achieved CR, one died during induction and one was refractory, 2 pts. discontinued study therapy. Non-hematologic adverse events (AE) grades 3/4 during induction (in ≥ 5% of pts. irrespective of causality) included infections (n=20), elevated transaminases or bilirubin (n=18) and gastrointestinal AEs (n=12). The spectrum of AEs was similar during consolidation, without concerns related to cardiovascular events. 24 pts. (61y; 55-69y) underwent allogeneic (9 MUD, 12 SIB, 3 Haplo) and 3 autologous SCT. 21 pts. received reduced intensity conditioning (including 8Gy TBI, n=11) regimens. Among all pts., relapse was the main cause of treatment failure (n=23; 17 BM, 2 CNS, 3 other sites, 1 na), 11 pts. died in CR (6 after HSCT), 34 are in ongoing CR. Based on Kaplan Meier analysis, EFS (events being resistant disease, relapse or death) at 12 months was 74%, with median follow-up of 39 (24-66) months for surviving pts., EFS and OS at 4 years was 42%, and 47%, respectively. By landmark analyses using median time to HSCT as cutoff, cumulative incidence of relapse in transplanted vs. non-transplanted pts. was 32% and 47%, OS at 4 years was 61% and 39%, median OS was not reached versus 3.6 years, respectively (p=ns). The proportion of pts. with a BCR-ABL1/ABL1 ratio ≤0.1% increased from 41% after induction to 86% after consolidation 2; that of pts. with undetectable or non-quantifiable BCR-ABL1 transcripts (sensitivity ≥10-4) increased from 14% to 58%. Conclusions. Nilotinib combined with low-intensity chemotherapy is well tolerated and highly effective in elderly pts. with Ph-positive ALL. OS and EFS compare favorably with previous similar studies testing imatinib or dasatinib. With 32% of pts. undergoing allogeneic HSCT and 61% survival at 4 years, transplantation is a viable option in this elderly cohort of pts.. Disclosures Ottmann: Celgene: Consultancy, Research Funding; Novartis: Consultancy; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Fusion Pharma: Consultancy, Research Funding. Pfeifer:Novartis: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sanhes:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goekbuget:Pfizer: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Celgene: Consultancy; Kite / Gilead: Consultancy; Amgen: Consultancy, Other: Travel support, Research Funding. Dombret:Jazz Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Shire-Baxalta: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Otsuka: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114552

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7