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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. 114, No. 22 ( 2009-11-20), p. 3288-3288

Abstract: Abstract 3288 Poster Board III-1 IM is approved for the treatment of AP-CML at 600mg daily. Clinical trials in which IM was evaluated in this setting have mainly enrolled patients (pts) who have failed prior therapies and the efficacy of the drug in newly diagnosed AP-CML has never been specifically studied. We collected data from 43 de novo pts with disease acceleration at diagnosis and treated with first-line IM. Thirty-three showed hematological acceleration (HEMAP) according to WHO 2002 or ELN 2006 criteria and 10 had cytogenetic acceleration only (CYAP), defined as the presence of chromosomal abnormalities additional (ACA) to the Philadelphia (Ph) chromosome. Ph variant translocations, loss of the Y chromosome and constitutional cytogenetic abnormalities were excluded from ACA definition. Ten out of 33 HEMAP pts (30%) had also ACA. ACA included Ph duplication (n=4), trisomy 8 (n=5), add(6) (n=3), monosomy 7 (n=1), del(5q) (n=1), t(3;21)(q26;q22) (n=1) and others (n=7). Median age at diagnosis was 51 years (19–67), 32 pts were males (75%) and 11 were females (25%). The median time from diagnosis to IM initiation was 15 days (0–140). The initial IM dose was 600mg/d (n=32) or 400mg/d (n=11). The median duration of IM therapy was 20 months (1–90). A sustained complete hematologic response (CHR) for at least 4 weeks was achieved in 38/43 pts (88.4%, 95% CI 78.4–99.3), including 29 HEMAP and 9 CYAP pts (87.9% versus 90%, not significant (ns)). The median time to achievement of CHR was 42 days (0–97). CHR was lost in 3 pts after 4, 6 and 10 months. Pts with lack or loss of CHR were initially classified as HEMAP (n=5) or CYAP (n=3), all except one harboured ACA at diagnosis. In addition, 4/7 screened pts had a BCR-ABL mutation (E255K n=3, E355G n=1) at the time of IM failure. A major cytogenetic response (MajCR) was observed in 31/43 patients (72.1%, 95% CI 58.1–86.1), and a complete cytogenetic response (CCR) was obtained by 27/43 pts (62.8 %, 95% CI 44.7–78.8), with 22 HEMAP pts and 5 CYAP pts (66.6% versus 50%, ns). The median time to reach CCR was 6 months (3–23). The rate of CCR in HEMAP pts with ACA was significantly lower than that in HEMAP pts without ACA (36.4% vs 80%, p=0.023). Eighteen pts with CCR (16 HEMAP pts and 2 CYAP pts) also gained a major molecular response (MMR: BCR-ABL/ABL ratio % IS ≤ 0.1%). The median time to MMR was 9 months (5–34). Seven pts subsequently lost their MajCR (CCR n=3, partial CR n=4) 3 to 31 months after first achieving it, 2 due to a poor compliance to IM and 5 due to acquired resistance. Of the latter, 4/5 had ACA at diagnosis and a BCR-ABL mutation emerged in 3/5 (E355G n=1, E255K n=1 and T315I n=1). Four pts (2 HEMAP and 2 CYAP) who failed to achieve CHR or CCR evolved toward blast crisis (BC) while on IM, after 1 to 11 months of treatment. The event-free survival (EFS) rate on IM was 57.1% (95% CI 41.4–72.7) at 24 months, events being defined as lack/loss of response, BC or death, whichever came first. The progression-free survival (PFS) rate on IM was 89.7% (95% CI 80–99.4) at 24 months, progression being defined as BC or death. EFS and PFS and did not significantly differ between HEMAP and CYAP pts but EFS at 24 months was significantly poorer in HEMAP pts with ACA at diagnosis than that in HEMAP pts without ACA (26% vs 74.7%, p=0.0055). Twenty-three out of 43 (53.5%) pts discontinued IM after a median duration of treatment of 11 months (1–90), because of treatment failure/progression (n=14), intolerance (n=8) or undetectable molecular residual disease (UMRD, n=1). For those on continuous IM therapy, the median observation time was 32 months (3–76). Following IM discontinuation, 15 pts were switched to second generation tyrosine kinase inhibitors (TKI) and 2 of them evolved toward BC and died, 3 pts underwent allogeneic hematopoietic stem cell transplantation, 4 pts received intensive chemotherapy with or without TKI and 1 was further transplanted, and the last pt with UMRD remained treatment-free. To conclude, although IM front-line induces substantial and durable responses in de novo AP-CML, our results suggest that there may be room for further improvement, especially in case of HEMAP together with ACA. The potential of other front-line therapies such as second generation TKI may be evaluated in this setting. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.3288.3288

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. 134, No. Supplement_1 ( 2019-11-13), p. 494-494

Abstract: The combination of 2GTKI+pegylated IFN-α (Peg-IFN) is an attractive approach for first-line treatment of CP CML, inducing high rates of deep molecular responses in phase II trials. Thus, we evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82). Newly diagnosed CP CML pts ≤65 y, without prior history of arterial occlusion were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone for 30 days (M-1→M0) 30 μg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 wks, upgraded to 45 μg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone for 4 more years unless pts enter treatment-free remission (TFR). The primary endpoint is the rate of MR4.5 by 1 y. As a secondary endpoint, pts reaching MR4.5 ≥2 y are allowed to stop NIL and enter a TFR phase in both arms. The trigger for treatment resumption is loss of MMR. All molecular assessments are centralised, quantifications are expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Two hundred pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. Median follow-up is 43.8 (34.3-55.9) Mo. Results are analysed in intention-to-treat. Sokal and EUTOS LTS scores were H in 25% and 2.5%, Int. in 33% and 16.5% and L in 42% and 81% pts respectively equally balanced. Median age is 46 (18-66) y, 18 pts (9%) had ACAs, all pts have a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (in B) and 88% of pts in A and 90.4% of pts in B at M1. CCyR rates at M3 were 63% vs 75% in A and B (p=ns), and BCR-ABL1 ≤1% at M6 were 87% in A vs 93% in B (p=ns). By M12, the rates of MMR were 68.1% vs 70.1% (p=0.44), MR4 were 34% vs 47.5% (p=0.041), MR4.5 were 15.9% vs 21.5% (p=0.049), MR5 11.7% vs 23.71% (p=0.023), in A vs B respectively. By M36 the rates of MMR were 83% vs 86.6% (p=0.31), MR4 were 70.2% vs 71.13% (p=0.50), MR4.5 were 37.2% vs 49.5% (p=0.05), MR5 33% vs 42.3% (p=0.12), in A vs B respectively The overall cumulative incidence of MR4.5 is superior in B (54.6 [43.7-65.5] %) vs A (44 [31.5-54]%) close to significance (unilateral Fisher test, p=0.05, see Figure). Seven patients were mutated by Sanger in A (5 Y253, 1 E255K, 1 T315I) vs 2 in B (2 T315I). One pt (A) progressed toward AP and then myeloid BC with a Y253H mutation, is still alive in CMR on Ponatinib. Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator decision 5), 1 pt died from cervix cancer (A). Median overall doses of NIL delivered by M36 were 600 mg/d in both arms (p=ns). The median overall dose of Peg-IFN delivered in B by M24 was 37.5 mg/wk. The overall rate of grade 3-4 hematologic toxicities was 22%; with 2% and 7% thrombocytopenia, 4% and 6% neutropenia, and 1% and 1% pancytopenia in A vs B respectively. Major grade 3-4 non-hematologic toxicities consisted in 9% of cardiac disorders in A (2 coronaropathies, 1 myocardial infarction, 2 thoracic pains, 2 atrial fibrillation, 1 bradycardia, 1 palpitations, 1 pericarditis) vs 8% in B (2 coronaropathies, 1 myocardial infarction, 3 atrial fibrillation, 1 palpitations, 1 pericarditis), 4% vascular disorders in A (1 thrombophlebitis + PE, 1 transient ischemic attack, 1 PAOD, 1 carotid stenosis) vs 3% in B (1 thrombophlebitis, 1 PAOD, 1 transient ischemic attack). Three % of gastro-intestinal disorders were observed in A (2 pancreatitis, 1 anal fissure) vs 6% in B (2 pancreatitis, 1 anal fissure, 1 abdominal pain, 2 cholecystectomies); 5% auto-immune disorders in B (1 recurrent pericarditis, 2 hemolytic anemia, 1 ITP, 1 thyroiditis); 5 and 8 pregnancies (2 pts + 3 partner Arm 1, 3 pts + 5 partner Arm B), despite recommended contraceptive methods. Secondary tumours were diagnosed in 4% (1 breast, 1 cervix, 1 thyroid, 1 neuroendocrine) in A vs 2% of pts (1 neuroendocrine and 1 testis) in B. Of note 8% psychiatric episodes were reported in B pts (2 unsuccessful suicide attempts), vs 2% in A. We observed 9% lipase elevations in A, 6% in B, 2% cholestatic episodes in A, 6% in B; 3% of transaminase elevations in A vs 2% in B. Infections were detected in 3% A vs 7% in B. The combination of NIL + Peg-IFN seems to provide somewhat higher MR4.5 rates by M36 in newly diagnosed CP CML pts without inducing significant higher toxicities than NIL alone. Whether this will translate in higher TFR rates is under evaluation. Final updated results at M36 will be presented Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Novartis: Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Huguet:Servier: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Charbonnier:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Legros:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria. Coiteux:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy. Roy:Incyte Biosciences: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Ame:Incyte Biosciences: Honoraria, Speakers Bureau. Rea:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria; BMS: Honoraria. Dulucq:Novartis: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. OffLabel Disclosure: Pegylated Interferon alpha 2 a is not licensed in this setting

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123674

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 166-166

Abstract: Abstract 166 Background Imatinib mesylate combined to pegylated interferon alfa 2a (Peg-IFN) has been reported to significantly enhance the molecular responses for de novo chronic phase chronic myeloid leukemia (CP-CML) patients compared to Imatinib alone in a Phase 3 study (Preudhomme et al. NEJM 2010). Second generation tyrosine kinase inhibitors (TKI2) such as nilotinib induce significantly higher levels of cytogenetic and molecular responses than imatinib as front line therapy for CP-CML (Saglio et al., NEJM 2010). Aims Test the combination of nilotinib + Peg-IFN as front line therapy in CP-CML patients in order to check the safety and evaluate the molecular response rates (EudraCT 2010–019786–28). Methods In this 2-step French national study, patients were assigned first to Peg-IFN (± HU) for a month at 90 mg/wk prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 mg/wk for ≥ 1 year. The primary endpoint was the rate of confirmed (on 2 datapoints) molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in %. Results In the first cohort, 40+1 patients (1 screen failure) were enrolled and a second cohort of 20 patients was planned once the last patient of cohort 1 attained 1 year of treatment, if the primary endpoint would have not been reached. The current median follow-up is 13.6 (10.1–16.3) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. Euro score was high for one patient. The median age was 53 (23–85) years. Two patients had a masked Philadelphia chromosome, 3 a variant form, and 1 had additional chromosomal abnormalities, all patients had a “major” BCR transcript. Five percent of patients were in CHR at 1 month of Peg-IFN and 100% at month (M) 2 (after 1 month of combination therapy). The rates of Complete Cytogenetic Responses (CCyR) at 3, 6, and 12 months of combination (i. e. at 2, 5, 8 and 11 months of TKI2) were 47%, 71%, 100% respectively on evaluable samples. The incidence of molecular responses are mentioned in figure 1. Of note, 87% of the patients had a BCR-ABLIS ≤10% at M3. The rates of molecular responses broke down by major molecular response (MMR): 27%, 4 log reduction (MR4): 36%, and ≥4.5 log BCR-ABL reduction (MR4.5, MR5 and undetectable): 21% with a total number of 84% patients in ≥MMR and beyond (17.5% and 67.5% in intention-to-treat respectively) at 1 year. Confirmed molecular results at 1 year will be presented. Nilotinib trough levels centrally analysed at M3, 6 and 12 for the vast majority of patients were ≥ 1000 ng/ml and Peg-IFN did not seem to impact on its pharmacokinetics. One patient went on unmutated myeloid blast crisis at M6 and is alive after allogeneic stem cell transplantation. Four additional patients were withdrawn from study: At M2 for non observance, at M6 for seizures related to an extra-dural hematoma, at M6 for recurrent grade 3 hepatic toxicity, at M9 for recurrent grade 3 pruritus. The median dose of Peg-IFN delivered to the patients during the first month was 90 (0–180) mg/wk, 45 mg/wk at M2, 3, 9, 12, and 33.75 mg/wk at M6. The median doses of nilotinib delivered to the patients were 600 mg daily at M2, 3, 6, 9, 12 and 15 as initially planned. The rate of grade 3–4 hematologic toxicities overall were anemia 2.5%, thrombocytopenia 41%, neutropenia 41% and pancytopenia 5%. These were observed mainly during M2 (16% neutropenia, 24% thrombocytopenia, 3% anemia), M3 (16% neutropenia, 13% thrombocytopenia, 3% pancytopenia) and M6 (12.5% neutropenia, 5% thrombocytopenia) and disappeared thereafter. Grade 3–4 toxicities occurred mostly during the first 3 months with 15% cholestatic episodes, 5% of ALAT elevation, 2.5% of lipase elevation, 2.5% arthro-myalgias, 2.5% abdominal pain without lipase elevation, 2.5% of depression. No PAO was observed and, to date, no dyslipidemia. Conclusion The combination of nilotinib and Peg-IFN seems relatively well tolerated despite frequent initial and transient hematologic and hepatic toxicities, and provides very high rates of molecular responses at 1 year and beyond. According to the initial methodology of this trial, the second cohort of patients will not be enrolled as the MR4.5 rates at M12 are beyond the initial expectations. A randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is warranted. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy. Roy:Novartis, BMS: Speakers Bureau. Huguet:Novartis, BMS: Speakers Bureau. Legros:Novartis, BMS: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:Novartis, BMS: Speakers Bureau. Guerci-Bresler:Novartis, BMS: Speakers Bureau. Rea:Novartis, BMS: Consultancy, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis, BMS: Speakers Bureau. Rousselot:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy, Speakers Bureau. Guilhot:Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Mahon:Novartis, BMS: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.166.166

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4039-4039

Abstract: Background Ponatinib, a third generation TKI, induces high rates of cytogenetic and molecular responses in heavily pre-treated CML patients (pts) resistant to ≥2 TKI and/or with a T315I mutation, especially in CP (J. Cortes at al., NEJM 2013). This agent induces diverse non-severe adverse events (AEs), a substantial proportion of pts experience severe arterial thrombotic events [(ATE) 17% by 3 years, J. Cortes et al., Haematologica 2015]. This agent is now licensed and it is mandatory to explore the rates of responses and ATE in the real-life setting. Aims We took the opportunity of the French ponatinib compassionate use program between May 2013 (end of PACE inclusions) and January 2014 (ponatinib license) to evaluate different outcomes in real-life conditions. Methods This is a multicenter observational retrospective study, designed to examine safety and efficacy of ponatinib in CML (any phase) resistant/intolerant to prior TKIs, in university and non-university hospitals, benefiting from the national ponatinib compassionate use program. Data were captured and validated following the rules and regulations of observational studies in France. Pts were analyzed in intention-to-treat, Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL are expressed as % IS in all centers. Standard clinical [gender, age, weight, body mass index (BMI), cardiovascular risk factors (previous events, tobacco abuse, high blood pressure, diabetes)], onset of any CV events before and during ponatinib treatment) and metabolic biological parameters (cholesterol, triglycerides) were collected. Results Thirty-five observations were collected in CP, 4 in AP and 5 in BC. We focused our analysis on the 35 CP pts only. There were 16 (46%) males and 19 females, with a median age of 53 (18-76) years at CML diagnosis and 59 (20-82) years at ponatinib initiation. Sokal scores were high in 13 (37%), intermediate in 12 (34%), low in 4 (12%) and unknown in 6 (17%); Euro scores were high in 6 (17%), intermediate in 15 (43%), low in 3 (9%) and unknown in 11 (31%); Eutos scores were high in 7 (20%), low in 20 (57%) and unknown in 8 (23%) pts. All pts harbored "major" BCR-ABL transcripts except one (e19a2). Regarding cardiovascular risk factors (CVRF) prior to ponatinib, 12 pts (34%) were treated for hypertension, 1 was diabetic, 6 (17%) had dyslipidemia (all on statins). Tobacco abuse was present in 8 (23%) pts and 14 pts had some pre-existing CVRF in total. Median weight just prior ponatinib was 66 (48-107) kg, and BMI was 24.2 (17.85-33) kg/m2. Thirteen (37%) pts were on anti-aggregants or anti-coagulants (AAG/C) prior to ponatinib. All pts had received imatinib first-line for a median of 29.5 (4-123) months, 20 (57%) dasatinib and 14 (40)% nilotinib as second-line, one pt developed a T315I after imatinib only; 21 (60%) had received all 3 TKIs prior to ponatinib. At ponatinib initiation, 7 (20%) harboured a T315I mutation, 7 (20%) other mutation(s) 20 (57%) none. In one case mutation screen was not performed. The trigger for ponatinib was resistance (hematologic, cytogenetic or molecular progression) in 26 (74%) pts, intolerance in 7 (20%) pts and both in 2 (6%) pts. Pts were initiated at a median of 45 (30-45) mg daily after a median of 79.5 (12-217) months of disease duration. The median follow-up on ponatinib was 26 (2-37) months. The cumulative incidence of major molecular responses was 29% at 3, 42% at 6, 56% at 12 and 70% at 18 months. The overall survival is shown in figure 1. Four pts died, 3 of disease progression and 1 of myocardial infarction. Six (17%) pts had grade 3-4 hematologic AEs imposing transient ponatinib withhold, and 14 (40%) had diverse grade 1-2 non-hematologic, non-CV AEs (pancreatic, hepatic, skin toxicities, no grade 3-4). ATEs occurred in 19 (54%) pts after a median of 5.8 (0.7-21.7) months of ponatinib, without CVRF in 10 (53%) pts and without AAG/C in 13 (68%) pts. CVRF and AAG/C had no significant influence here on ATEs onset in univariate Cox model (p=0.76 and 0.37 respectively). Lipids and HbA1c were not modified on ponatinib. Overall 43% of pts stopped ponatinib for toxicity. Conclusion In the French compassionate use program in CP-CML patients resistant or intolerant to previous TKIs, ponatinib displayed strong efficacy, as previously described. In this unselected population of patients, ATEs were confirmed to represent the main tolerance concern in the real life setting. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coiteux:Novartis: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau. Charbonnier:Novartis: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau. Huguet:Novartis: Consultancy, Research Funding; PFIZER: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau. Legros:Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. DeFrance:Ariad: Consultancy. Mahon:ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rea:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4039.4039

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. 114, No. 22 ( 2009-11-20), p. 3080-3080

Abstract: Abstract 3080 Poster Board III-17 Introduction The combination of imatinib with high-dose chemotherapy has been shown as very promising in patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by several groups. Reported studies all demonstrated a higher response rate and an improved outcome as compared to the pre-imatinib era, but generally with a short follow-up. This was also observed in our GRAAPH-2003 study with complete remission (CR) rate, 18-month disease-free survival (DFS), and 18-month overall survival (OS) of 96%, 51%, and 65%, respectively (de Labarthe et al. Blood 2007). We report here the long-term results of this study with a longer median follow-up of 46 months. Patients & Methods From 2004 to 2005, 45 patients with newly-diagnosed Ph+ ALL (median age, 45 years; range, 16-59 years; 25 males and 20 female) were included in the GRAAPH-2003 study. Briefly, imatinib was started with HAM consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders. Imatinib was administered until allogeneic (if a matched familial donor or an unrelated donor matched at 9 or 10 of 10 HLA antigens) or autologous (if no donor and a good molecular response) stem cell transplantation (SCT). Results were compared with the results of the previous pre-imatinib LALA-94 trial (Dombret et al. Blood 2002). Results When compared to the former LALA-94 study, 4-year OS and DFS were estimated at 52% (36-66) versus 20% (14-26) (p=0.0001) and 43% (27-58) versus 20% (14-28) (p=0.002) in the GRAAPH versus LALA cohorts, respectively. In the GRAAPH-2003, all the 22 CR patients with a donor may receive allogeneic SCT in first CR. In addition, 10 CR patients without a donor but low post-HAM BCR-ABL level received autologous SCT. No significant differences were observed between the donor and the no-donor groups in terms of OS (55% versus 54% at 4 years; p=0.80) and DFS (47% versus 39% at 4 years; p=0.40). This result was partly explained by the good outcome observed in patients who received autologous SCT. The 4-year OS in the allogeneic SCT, autologous SCT, and no SCT groups were 55%, 80%, and 25%, respectively (auto versus allo, p=0.16; auto versus no SCT, p=0.008; allo versus no SCT, p=0.05). The 4-year DFS in the allogeneic SCT, autologous SCT, and no SCT groups were 47%, 50%, and 25%, respectively (auto versus allo, p=0.91; auto versus no SCT, p=0.27; allo versus no SCT, p=0.17). Overall, 4-year cumulative incidences of relapse and death in CR were estimated at 24% (14-40) and 32% (20-49), respectively, underlying the toxicity of the whole GRAAPH-2003 strategy. Notably, 7 of the 22 allografted patients died in CR, as compared to only 1 of the 10 autografted patients. Conclusion We show here that the beneficial impact of the combination of imatinib with chemotherapy is not transient and is preserved in the long term. Taking into account the good outcome of patients receiving autologous SCT and the toxicity of allogeneic SCT, the place and timing of SCT, as well as the optimal chemotherapy to be delivered with imatinib prior to SCT, must be carefully re-evaluated in further prospective trials. Disclosures Dombret: cejgene: 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.V114.22.3080.3080

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 363, No. 26 ( 2010-12-23), p. 2511-2521

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJMoa1004095

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 2010

detail.hit.zdb_id: 1468837-2

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2553-2553

Abstract: Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19] , p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146412

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Experimental Hematology, Elsevier BV, Vol. 67 ( 2018-11), p. 41-48

Type of Medium: Online Resource

ISSN: 0301-472X

URL: Article

DOI: 10.1016/j.exphem.2018.08.006

Language: English

Publisher: Elsevier BV

Publication Date: 2018

detail.hit.zdb_id: 2005403-8

In: Bulletin du Cancer, Elsevier BV, Vol. 103, No. 2 ( 2016-02), p. 180-189

Type of Medium: Online Resource

ISSN: 0007-4551

URL: Article

DOI: 10.1016/j.bulcan.2015.11.008

Language: French

Publisher: Elsevier BV

Publication Date: 2016

detail.hit.zdb_id: 213270-9