No abstract

Universal plasma was equivalent to ABO-matched plasma with respect to safety and tolerability. Eliminating the risk of ABO incompatibility, this universal plasma represents an advance over blood group-specific plasma.

Background Tyrosine kinase inhibitors (TKIs) are the standard of care for pts with CP-CML. Current recommendation is to continue TKI therapy indefinitely but previous studies indicate that pts with deep and sustained molecular responses (MRs) on imatinib (IM) may achieve long-lasting TFR. Nilotinib (NIL) at 300mg BID induces higher rates of deep MRs compared to IM and high dose NIL (400mg BID) enables a substantial proportion of pts who do not obtain MR4 (BCR-ABL1IS £ 0.01%) or MR4.5 (BCR-ABL1IS £ 0.0032%) with IM to reach such deep MRs levels, potentially compatible with TFR. However, optimal duration of treatment with NIL to ensure the highest rate of TFR after treatment discontinuation is unknown. Objective ENESTPath was designed to assess the optimal duration of NIL therapy that is necessary to achieve and maintain TFR upon treatment discontinuation in pts pretreated with IM. Methods ENESTPath is a randomized, phase III study enrolling CP-CML pts who after at least 2 years (yrs) of IM therapy achieved a complete cytogenetic response (CCyR), but not yet a MR4. After enrollment, pts were assigned to receive NIL at 300 mg BID for 2 yrs or 3 yrs (Arm 1 and Arm 2, respectively). Patients who will obtain a stable MR4 or better for at least 12 months (mo) will enter the TFR phase. Primary endpoint is to evaluate the proportion of pts in both arms who will remain in TFR for ≥1 yr after NIL discontinuation. Results 620 pts were enrolled in the study between May-2013 & Apr-2015. In this interim analysis, the first 300 pts (mean age 50.8 yrs; 63.7% male) enrolled and treated with NIL for ≥1 yr have been included. Baseline characteristics are detailed in the Table. By 12 mo of NIL treatment, cumulative incidences of newly acquired MR4 and MR4.5 were 57.4% and 30.5%, respectively. Further analysis of MR4 achievement showed that pts with a major molecular response (MMR: BCR-ABL1IS >0.01% - ≤0.1%) at baseline had a higher probability to achieve a MR4 than those lacking MMR at baseline, with a cumulative incidence of MR4 by 12 months of 64.8% and 30.8%, respectively (Figure). Adverse events (AEs) were mostly of grade 1-2, manageable with supportive care or NIL dose interruption/reduction and included pruritus (19%), headache (9%), skin rash (9%), upper abdominal pain (8%) and constipation (7%). Grade 3-4 hematologic AEs were uncommon. The incidence of grade 3-4 laboratory abnormalities was low: lipase increase, hyperglycemia, ALT and AST increase, hyperbilirubinemia and hypercholesterolemia reported in 3.7%, 1.3%, 1%, 0.7%, 0.3%, 0.3% pts, respectively. Grade 3-4 ischemic cardiovascular events were experienced by 5% of pts including peripheral artery occlusive disease (1.7%) and coronary artery disease (3.7%) (1 pt experienced both AEs). Sub-analyses aiming to evaluate the impact of baseline SCOREa CV risk factor on the onset of arterial ischemic events are currently ongoing. Results on 168 pts showed grade 3-4 ischemic CV events in 19% of pts who were at very high or high risk (n = 47) compared to 1.7% of in pts with moderate or low risk (n = 121). During the first 12 mo, 48 (16%) pts discontinued NIL therapy: 32 discontinued due to AEs/laboratory abnormalities, 12 withdrew consent, 4 due to other reasons (protocol deviation, pregnancy and non-compliance). No patients left the study due to progression to AP/BP. Till date there were no on-treatment deaths. Conclusions This interim analysis shows that a switch to NIL at lower doses than in prior studies (300mg BID instead of 400mg BID) induces high rates of MR4 and MR4.5 in pts without such MR levels on IM. The safety profile of NIL at 300mg BID is consistent with that described in other prospective studies.Thus a switch to NIL for pts not achieving a deep MR during IM therapy is predicted to substantially increase the probability of achieving TFR requirements. A longer follow-up is necessary to assess what may be the best duration of NIL prior to treatment discontinuation. aRisk factors evaluated by applying the SCORE chart proposed by the European Society of Cardiology Table 1. Table 1. Figure 1. Figure 1. Disclosures Rea: Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cross:Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hellman:Novartis: Research Funding; BMS: Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Almeida:Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy. Dezzani:Novartis: Employment. Pellegrino:Novartis: Employment. Costantini:Novartis: Employment. Walasek:Novartis: Employment. Saglio:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Steegmann:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Baccarani:NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

No abstract

Objectives To analyze the molecular response during the first trimester of nilotinib therapy in newly diagnosed CML-CP patients. Hypothesis The values of BCR-ABL ratios during the first trimester of nilotinib treatment, and the kinetic of their descent, could be predictive of molecular response thereafter. Patients ENEST1st (NCT01061177) is an open-label study of nilotinib 300 mg twice daily in adults with newly diagnosed BCR-ABL+ CML-CP. Imatinib pretreatment was not allowed. Methods BCR-ABLIS and BCR-ABL/GUS ratios were measured previously to nilotinib, and fortnightly thereafter until the 3rd month (m), and at 6, 12 and 18 m. Sokal, Euro and Eutos scores were calculated with data at diagnosis. BCR-ABL values were centrally measured in an ELN-EUTOS certified laboratory. Molecular response was classified by ELN2013 recommendations. As the linearity of values of BCR-ABL using ABL as control is questionable, when ratios are higher than 10%, only baseline BCR-ABL/GUS ratios were used when analyzing the molecular response using GUS as control. The kinetic of the descent was calculated using the ratio of a given time compared with that of an earlier time, and measuring slopes. Logistic regressions and ROC analysis have been used, calculating positive and negative predictive values (PPV and NPV) Results 61 patients were included. 1 patient was excluded of the analysis because of lack of molecular data (baseline). Out of 60 patients, 10 abandoned during the first 18 m because of AE’ s. Those patients have been classified as non-responders after the time they went off-study. Risk distribution: Sokal (L, I, H): 57%, 32%, 11.7% Euro: 52%, 45%, 3%) Eutos (L, H): 92%, 8%). Outcomes and Molecular response: No patient died or transformed during the follow-up. MR4.5 at 18 M has been obtained in 30% of the patients. The ELN 2013 molecular milestones for optimal response at 3,6,12 and thereafter were obtained in 97%, 93%, 83%, and 70%, respectively.(Table) Predictive variables of response: (Table). Major molecular response (²0.1%) (BCR-ABL/ABL, BCR-ABL/GUS). At 3MBaseline BCR-ABL/GUS ratios were significantly different between responders and non-responders (22,1±23,1 vs 41,5± 38,1, p=0.05). For both control genes, the multivariate analysis disclosed that the independent and significant variable was the ratio at 45d. The ROC analysis disclosed a cut-off of 3.28 (PPV: 83% NPV: 80%). [OR: 20(4.4- 90) p<0.00001]. For BCR-ABL/GUS it was 3.5 (PPV: 87% NPV: 73%). At 6M and at 12 M: For both control genes, only the ratio at 3M and the ratio at 6 M were independently associated, respectively. At 18 M; With BCR-ABL/ABL, only the ratio at 12M was the independent and significant variable. Variables associated with MR4.5 at 18 m (BCR-ABL/ABL). The ratios at 1M, 1.5 M, and 2 M were significantly associated with the MR4.5 at 18 M. In the multivariant analysis the only independent variable associated with this response was the BCR-ABL ratio at 2M. The ROC curve disclosed a cut-off of 1.52 (PPV: 91% NPV: 59%). When including this variable as dichotomic, in a multivariant analysis, was the only significant one [OR: 14(3.2-60) P=0.0004)]. The correspondent cut-off at 3M was 0.1 (PPV: 84% NPV: 60%); [OR: 7,7(2.2-27) P=0.001]. Discussion Our results show that, in newly diagnosed patients, nilotinib obtained responses very quickly, and the proportions of patients having an optimal ELN2013 response at 3M (BCR-ABLIS² 10%), and at 6M (BCR-ABL IS ² 1%) were 97% and 93%. For obtaining a MMR at 3M, the only significant cut-off was at 45 d. For subsequent MMR, the only independent variable was the ratio at the most immediate earlier point. Besides, our results show a similar proportion of responses when using GUS as control gene, and similar predictive cut-offs in the ROC analysis of MMR at 3 and 6 M. Nilotinib treatment obtained 30% of MR4.5 at 18M. Ratios at 1M, 1.5 M, and 2 M were significantly associated with this response, but the only independent variable was the BCR-ABL ratio at 2M. At 2 M, having a ratio higher than 1.52 % will be linked with a 91% probability of not obtaining a MR4.5 at 18 M. Disclosures: Steegmann: Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Casado Montero:Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Echeveste:Celgene: Consultancy; Novartis: Consultancy. Garcia-Gutierrez:Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Ruiz:Novartis: Employment. Walasek:Novartis: Employment.