PEDRO ENRIQUE DORLHIAC LLACER
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
4 resultados
Resultados de Busca
Agora exibindo 1 - 4 de 4
- Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results(2017) HUGHES, T. P.; LEBER, B.; CERVANTES, F.; SPECTOR, N.; PASQUINI, R.; CLEMENTINO, N. C. D.; SCHWARER, A. P.; DORLHIAC-LLACER, P. E.; MAHON, F-X; REA, D.; GUERCI-BRESLER, A.; KAMEL-REID, S.; BENDIT, I.; ACHARYA, S.; GLYNOS, T.; DALAL, D.; BRANFORD, S.; LIPTON, J. H.
conferenceObject Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update(2012) KHOURY, H. Jean; GAMBACORTI-PASSERINI, Carlo; KANTARJIAN, Hagop M.; KIM, Dong-Wook; MARIN, David; DORLHIAC-LLACER, Pedro E.; ZARITSKEY, Andrey; NAVARRO, Juan; BULLORSKY, Eduardo O.; ASSOULINE, Sarit; LEIP, Eric; KELLY, Virginia; TURNBULL, Kathleen; BESSON, Nadine; CORTES, Jorge E.Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ~1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates- Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib(2014) HUGHES, Timothy P.; LIPTON, Jeffrey H.; SPECTOR, Nelson; CERVANTES, Francisco; PASQUINI, Ricardo; CLEMENTINO, Nelma Cristina D.; LLACER, Pedro Enrique Dorlhiac; SCHWARER, Anthony P.; MAHON, Francois-Xavier; REA, Delphine; BRANFORD, Susan; PURKAYASTHA, Das; COLLINS, LaTonya; SZCZUDLO, Tomasz; LEBER, BrianPatients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after >= 2 years on imatinib were randomized to nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) <= 0.0032%; MR4.5) and those without major molecular response at study start, MR4.5 by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the nilotinib and imatinib arms, respectively. No patient in the nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the nilotinib arm, as expected with the introduction of a new drug vs remaining on a well-tolerated drug. The safety profile of nilotinib was consistent with other reported studies. In summary, switching to nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www. clinicaltrials.gov as # NCT00760877.
conferenceObject NILOTINIB INDUCES DEEPER MOLECULAR RESPONSES VS CONTINUED IMATINIB IN PATIENTS WITH PH plus CHRONIC MYELOID LEUKEMIA (CML) WITH DETECTABLE DISEASE AFTER=2 YEARS ON IMATINIB: ENESTCMR 12-MONTH RESULTS(2012) CERVANTES, C.; HUGHES, T.; ETIENNE, G.; SOUZA, C. A. De; LLACER, P. E. Dorlhiac; SCHWARER, A.; LEBER, B.; LIPTON, J.; SPECTOR, N.; REYNOLDS, J.; COLLINS, L.; SZCZUDLO, T.; REA, D.