Introduction
Vitamin C is an essential micronutrient playing crucial roles in human biology. Hypovitaminosis C is defined by a plasmatic ascorbemia below 23 µmol/L and is associated with numerous ...outcomes such as cardiovascular diseases, cancers or neurocognitive disorders. Numerous risk factors are common among older adults making them particularly susceptible to hypovitaminosis C. These risk factors include reduced vitamin intakes, higher vitamin metabolism related to polypathology, and iatrogeny because of polypharmacy. However, the precise prevalence of hypovitaminosis C and its risk factors are poorly documented within the geriatric population.
A better knowledge of hypovitaminosis C prevalence and risk factor may lead to improving the vitamin C status among older people and prevent its consequences.
Method and analysis
To answer these questions, we designed a monocentric cross-sectional study in a population of older hospitalised patients in Lyon, France. A sample size of 385 patients was needed to estimate hypovitaminosis C prevalence. The study was proposed to all eligible patient aged more than 75 years old entering the participating acute geriatric unit. The plasmatic vitamin C status was systematically assessed for participating patients, and variables part of the medical and geriatric evaluation were collected. For patients with severe vitamin C depletion, an oral supplementation and a follow-up phone call were organised to ensure treatment completion and tolerance.
Ethics and dissemination
The protocol has been approved by an independent national ethics committee and meets the methodological requirements. Final outcomes will be published in a peer-reviewed journal and disseminated through conferences.
Trial registration number
NCT05668663
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Sustained imatinib treatment in chronic myeloid leukemia patients can result in complete molecular response allowing discontinuation without relapse. We set out to evaluate the frequency of complete ...molecular response in imatinib de novo chronic phase chronic myeloid leukemia patients, to identify base-line and under-treatment predictive factors of complete molecular response in patients achieving complete cytogenetic response, and to assess if complete molecular response is associated with a better outcome. A random selection of patients on front-line imatinib therapy (n=266) were considered for inclusion. Complete molecular response was confirmed and defined as MR 4.5 with undetectable BCR-ABL transcript levels. Median follow up was 4.43 years (range 0.79-10.8 years). Sixty-five patients (24%) achieved complete molecular response within a median time of 32.7 months. Absence of spleen enlargement at diagnosis, achieving complete cytogenetic response before 12 months of therapy, and major molecular response during the year following complete cytogenetic response was predictive of achieving further complete molecular response. Patients who achieved complete molecular response had better event-free and failure-free survivals than those with complete cytogenetic response irrespective of major molecular response status (95.2% vs. 64.7% vs. 27.7%, P=0.00124; 98.4% vs. 82.3% vs. 56%, P=0.0335), respectively. Overall survival was identical in the 3 groups. In addition to complete cytogenetic response and major molecular response, further deeper molecular response is associated with better event-free and failure-free survivals, and complete molecular response confers the best outcome.
Nilotinib is now recommended for patients with newly diagnosed chronic myeloid leukaemia in chronic phase and leads to important rates of molecular response 4·5 log (MR(4·5)), allowing the prospect ...of therapy cessation. However, most patients do not reach this criterion and nilotinib is taken for lengthy periods, resulting in chronic or late-onset adverse events. Nilotinib combined with interferon might further increase rates of MR(4·5), avoid late side-effects, and allow therapy cessation. In a phase 2 trial we aimed to assess the feasibility, safety, and deep molecular response of the combination of nilotinib (600 mg daily) and peginterferon alfa-2a in newly diagnosed patients with chronic-phase chronic myeloid leukaemia (CML).
In a non-randomised, open-label, phase 2 trial, we enrolled adult patients (age ≥18 years) without any organ failure who had BCR-ABL-positive, chronic-phase CML, at diagnosis. After a priming procedure with 90 μg per week of peginterferon alfa-2a alone for a month, we gave patients peginterferon alfa-2a 45 μg per week combined with nilotinib 600 mg daily until 24 months after interferon initiation. The primary endpoint was the cumulative incidence of MR(4·5) at 12 months after initiation of peginterferon alfa-2a. Data were analysed by a modified intention-to-treat principle. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-019786-28.
Between March 24, 2011, and Sept 27, 2011, we enrolled 42 patients. One patient withdrew consent before receiving any study treatment so was excluded from analysis; 41 patients received treatment with peginterferon alfa-2a and nilotinib. At 12 months, seven (17%) patients had achieved MR(4·5). Haematological and hepatic adverse events were frequent-with grade 3-4 neutropenias occurring in ten (24%) patients, grade 3-4 thrombocytopenias occurring in ten (24%) patients, grade 3-4 cholestatic events occurring in seven (17%) patients, and grade 3-4 elevations in aspartate aminotransferase or alanine aminotransferase occurring in three (7% patients-particularly during the first 3 months. However, 30 (73%) patients remained on interferon therapy at 1 year. Three grade 3-4 cardiac events (7% of patients, all coronary stenoses) occurred at later timepoints.
The combination of peginterferon alfa-2a resulted in good molecular responses in patients. Despite substantial toxic effects, most patients remained on the study drugs for more than a year. This combination should now be tested in a randomised controlled trial.
Novartis Pharma.
Background
Management of pregnant patients with BCR‐ABL‐positive leukemia is challenging. Managing a patient who has been diagnosed while pregnant requires a different approach as compared to a ...patient who plans to become pregnant while on the treatment with tyrosine kinase inhibitor (TKI). Interferon (IFN)‐alpha is a useful option in both situations due to teratogenic potential of TKIs.
Methods
We presented a series of 12 successful pregnancies in 11 women with BCR‐ABL‐positive leukemia, whose leukemia was managed with IFN‐alpha throughout their pregnancy.
Results
All children have normal growth and development. All patients remained at least in hematological response and could start or resume TKI after delivery or breastfeeding.
Conclusion
Because of the increased risk of teratogenicity and spontaneous abortion in female patient with pregnancy, when receiving TKI, IFN‐alpha can be considered a safe drug to be administered throughout pregnancy and could represent the drug of choice in this situation during the era of TKI therapy.
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
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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.
Pegylated Interferon alpha 2 a is not licensed in this setting
Background
We previously demonstrated that the combination of Nilotinib (NIL) + Pegylated IFN-a2a (Peg-IFN) is able to induce high deep molecular response rates in chronic phase CML (CP CML) ...patients, as first-line therapy (Nicolini FE et al., Lancet Haematol. 2015).
Aims
Assessment of the molecular responses obtained with the same combination vs NIL alone prospectively, in newly diagnosed CP-CML. (EudraCT 2013-004974-82).
Methods
Patients (pts) ≤65 years with no history of arterial damage were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone (± HU) for 30 days (M-1 to M0) 30 mg/wk as a priming, prior to a combination of NIL 300 mg BID + Peg-IFN 30 mg/wk 2 weeks, upgraded to 45 mg/wk thereafter if proper tolerance for up to 2 years (M0 to M24, arm B) followed by NIL alone for 2 more years. The primary endpoint was the rate of molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised, quantifications were expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control.
Results
Two hundred and one pts were randomized (100 in arm A, 101 in arm B), 65 males in both arms, 35 females in arm A, 36 in arm B. The median follow-up is 20.6 (9.1-34.7) months. Results are analysed in intention-to-treat. Sokal scores were high in 25%, intermediate in 36% and low in 39% of pts; Euro scores were high in 13%, intermediate in 44% and low in 43% of pts; Eutos LTS scores were high in 2%, intermediate in 17%, and 81% low; equally balanced in the 2 arms The median age was 46 (18-66) years, equally balanced. Eight (4%) pts had a cryptic Philadelphia chromosome, 12 (6%) a variant form, and 15 (7.5%) had ACAs, all pts had a “Major” BCR transcript. CHR was obtained in 9.6% of pts at M0 (arm B) and in 88% of pts in arm A and 90.4% of pts in arm B at M1. The rates of CCyR at M3 were 63% vs 65% in arms A and B, and BCR-ABL1≤1% at M6 were 83% in arm A vs 86% and arm B, on evaluable samples. The incidence of molecular responses are shown in Fig. 1.
Of note, 90% of the pts had a BCR-ABL1 ≤10% at M3 in arm A vs 84% in arm B (p=ns). By M12, the rates of MMR were 69.9% vs 72.4% (p=0.079), MR4 were 34.65% vs 47.9% (p=0.094), MR4.5 were 17.9% vs 24.11% (p=0.272), MR5 12.1% vs 22.31% (p=0.075), in arm A and arm B respectively. Data from 11 pts in arm A and 16 in arm B at M12 are still pending. Definitive results at 1 year will be presented. One pt progressed toward accelerated phase in arm A with a Y253H mutation. Fifteen pts were withdrawn from study in arm A (toxicity 5, other cancer 2, failure 8) and 12 patients from arm B (toxicity 6, failure 6), no pt died. Interestingly, 5 mutated (ie. failure) pts were found in arm A (3 Y253H, 1 E225K, 1 F317L), vs only 1 pt (T315I) in arm B. The median dose of Peg-IFN delivered in arm B during the first month is 30 (0-30) mg/wk, 30 (0-45) mg/wk at M2, 45 (0-45) mg/wk at M3, 37.5 (0-45) mg/wk at M6, 30 (0-45) mg/wk at M9 and 12. The median doses of NIL delivered were 600 mg daily at M2, 3, 6, 9, 12 as initially planned in both arms. The rate of grade 4 hematologic toxicities overall was 15%, with no anemias, 1% and 4% thrombocytopenias, 3% and 4% neutropenias, 0% and 1% leucopenias, and 0 and 1% pancytopenias in arms A and B respectively. Grade ¾ non-hematologic toxicities consisted in 4% of cardiac disorders in arm A (1 coronaropathy, 2 thoracic pains and 1 atrial fibrillation) vs 1% in arm B (palpitation), 2% vascular disorders in arm A (1 pulmonary embolism, 1 transient ischemic attack) and 1% in arm B (PAOD). Three % of gastro-intestinal disorders in arm A (resolutive pancreatitis) vs 1% in arm B (anal fissure); 1% of skin disorders in arm A; 2% auto-immune disorders in arm B (1 recurrent pericarditis, 1 hemolytic anemia); 2 and 5 pregnancies (of the partner except 1) were observed in arm A and B respectively, despite recommended contraceptive methods. We observed 10% lipase elevations in arm A, 3 in arm B, 2% cholestatic episodes in arm A, 1% in arm B; 1% of transaminase elevations in each arm. There were 2% depressive episodes in arm B, 1% in arm A; infections were detected in 1% arm 1 and 3% in arm B. Finally 3 intercurrent cancers were detected in arm A (cervix, breast, thyroid).
Conclusion
The combination of NIL + Peg-IFN seems to provide slightly deeper molecular responses rates (especially MR5) by M12, but so far not significantly, in newly diagnosed CP CML pts without increasing the rate of more frequent early SAEs in such a setting. Definitive results at M12 will be updated for the meeting.
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Nicolini:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Etienne:Incyte: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Research Funding. Guerci-Bresler:BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Charbonnier:Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Legros:BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Coiteux:Incyte: Speakers Bureau; BMS: Speakers Bureau. Cony-Makhoul:BMS: Speakers Bureau. Rousselot:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding. Guyotat:BMS: Speakers Bureau. Ianotto:Novartis: Other: Grant. Rea:BMS: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Mahon:Pfizer: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.
Despite its high efficacy on CML, long-term exposure to nilotinib, a second generation tyrosine kinase inhibitor (TKI2), has been reported to increase the onset of arterial cardiovascular events ...(CVE) in chronic phase (CP) CML patients (pts), especially in pts with cardiovascular risk factors. However, some pts without any cardiovascular risk factors may experience arterial thrombotic events and the pathogenesis of this phenomenon remains obscure. Homocystein (HC) is a key sulphured amino-acid derived from methionin, independently associated with increased frequencies of thrombo-embolic events, early arteriosclerosis and increased cardiovascular mortality (Nygard NEJM 1997). In addition, in vitro, this amino-acid induces the proliferation of smooth muscle cells, endothelial cell dysfunction, increased collagen synthesis and exerts pro-inflammatory rearrangements within the arterial wall.
In the present study, we wanted to determine if hyperhomocysteinemia might influence the onset of cardio-vascular events in a series of 114 CP CML pts on nilotinib. We have prospectively analysed in a multicentric study, on-nilotinib cohorts of CP CML pts between September 2011 and July 2014 with standard clinical assessments height, weight, body mass index (BMI), onset of any CV events, and basic routine blood metabolic laboratory assessments (fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycosylated haemoglobin, homocysteinemia (Biorad kit on HLPC on Summit Dionex system, Thermo Fischer scientific, France), vitamines B9 and B12. All the 114 pts were in CP-CML on nilotinib 43 as first-line, 71 as second-line or more, since a median of 51.5 (3-164) months, 49 were males, with a median age of 51.7 (18-81) at CML diagnosis and 58 (82-20) at nilotinib initiation. Twenty-eight (24.5%) pts presented some CV risk factors prior to nilotinib initiation, and 24 (21%) had an active tobacco abuse at assessment (4 patients unknown). Median weight was 69 (44-149) kg and median BMI was 24.5 (16.5-46) kg/m2 (8 patients >30). Overall, 21 (18.5) pts presented new or worsened pre-existing CVE on nilotinib after a median follow-up of 51.5 months since TKI2 initiation. These CVE occurred after a median of 47 (7.5-82.3) months with a regular increase along the years (Cumulative incidence (CI) 3% at 1 year, 4.12% at 2, 5.15% at 3, 9.30 at 5 and 20.62% at 8.3 years). In total, 3 pts died, 2 from brain stroke, 1 from sudden death in a pt with a history of myocardial infarction. In an univariate analysis we compared our cohort of nilotinib pts to a similar cohort of 17 pts on imatinib as control median age 56 years since CML diagnosis (p=ns), median duration of imatinib 39 months (p=ns), median weight 70.5 kg (p=ns), BMI 25.9 kg/m2 (p=ns). None of these imatinib pts had shown any CVE during follow-up. HC was significantly lower in imatinib-treated pts (p=0.029), in female pts (p=0.018) and increased with age (p<0.001), fasting glucose (p=0.001), glycosylated haemoglobin (p=0.027) were significantly lower too. There was no correlation between HC and cholesterol (total, HDL, LDL). We constructed in the nilotinib cohort a ROC curve to determine the HC cut-off threshold for CVE which was 13.75 mmol/l AUC=0.68 (95% CI: 0.54-0.82), sensitivity 65%, specificity 71%. We looked at the CI of CVE according to the HC levels, segregating the pts according to the HC threshold. There was a significant difference (p=0.003) in the incidence of CVE in patients on nilotinib according to the HC level, as shown on figure 1.
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The CI of CVE was significantly higher in pts on nilotinib 800 mg daily (38% at latest follow-up) versus pts on ≤600 mg daily, (10%, p=0.005, Gray test). Finally multivariate analysis identified age p<0.001, HR 1.05 (95% CI 1.02-1.09), 800 mg daily nilotinib dose p=0.0049, HR 7.08 (95% CI 1.81-27.6), and HC p=0.043, HR 1.11 (95% CI 1.03-1.19), with an increased risk of CVE on nilotinib.
In conclusion, nilotinib seems to favour CVE in the long-term in CP CML pts, especially in patients with CV risk factors, and these CVE are specifically linked to higher doses of nilotinib and high levels of homocysteinemia. This marker could represent a useful tool to detect pts at risk of arterial CVE on nilotinib. Whether hyperhomocysteinemia is one of the causes of CVE of a consequence of nilotinib treatment remains to be determined.
Michallet:Genzyme: Consultancy; Oseus: Consultancy; BMS: lectures, lectures Other; Novartis: lectures, lectures Other; MSD: lectures Other. Etienne:Novartis: Consultancy; BMS: lectures, lectures Other. Nicolini:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria.
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Introduction
Imatinib has indeed revolutionized the treatment of chronic myelogenous leukemia (CML) since more than 15 years now, especially in CP. The first patients (pts) in this setting were ...treated with this compound within the IRIS phase III trial from Novartis, started in January 2000. Regular updates of the results of this study have been presented during various meetings until year 7, and academic studies have recently reported the outcomes of IM first-line CP CML pts after 66 months follow-up. However, little is known about the very long-term outcomes (>8 years) of such first-line pts and these data might be of interest while generic forms of IM will be soon launched in this setting.
In this study, we aimed to look at long-term outcomes in terms of efficacy and toxicities in first-line CP CML pts treated with branded form of IM (Glivec®).
Methods
This is a comprehensive retrospective analysis of first-line CP CML pts treated with IM first-line 400 mg daily since diagnosis and followed in 2 university reference centers for CML between 2000 and 2015, inside or outside academic or industrial clinical trials. All living pts have given their agreement for participation in this retrospective analysis. Pts have been analyzed in intention-to-treat, CML was defined according to ELN criteria CP, accelerated phase (AP) and blast crises (BC), Sokal, Euro and EUTOS scores have been calculated as published. Molecular biology tests have been performed according to ELN guidelines and BCR-ABL1/ABL1 were expressed as % on the international scale and 3 ELN conversion factors have been applied successively along time according to material exchanges performed with the central European laboratory in Mannheim. Cytogenetic and molecular responses have been defined according to the ELN criteria. Overall survival (OS) was calculated from the date of IM initiation until death at any time and for any reason; until progression to AP or BC at any time for progression-free survival (PFS); and until death, progression to AP or BC, failure on IM or IM treatment discontinuation for any cause including treatment-free remission (TFR), for event-free survival (EFS). The cut-off date for this analysis was the 20th of July 2,015.
Results
At time of analysis, 120 pts could be analyzed, with a median follow-up of 85.5 (1-194) months, 70 (58%) were males, with a median age of 55 (11-85) at IM initiation. Sokal score was high for 24(20%) pts, intermediate for 58 (49%), low for 34 (30.5%), unknown in 4 (0.5%) pts. Four (3.5%) pts had a variant Ph chromosome, 7 (6%) with additional chromosomal abnormalities, and 2 a masked Ph chromosome, 6 harbored atypical BCR-ABL1 transcripts excluded from analysis. Early molecular response (M3) was achieved in 86 (72%) pts, unreached in 20 (16%) pts, and unknown for 15 (12.5%) pts. It was predictive of Major Molecular Response (MMR) at 12 months (p=0.01, OR 5.35, 95%CI 1.3-31.94), for MR4 rates at 24 months (p=0.03, OR 7.35 95%CI 1-328) and for EFS (p=0.006) but not for OS and PFS in a multivariate Cox model analysis. MMR was achieved in 42% of evaluable pts at 12 months. Eutos, Euro and Sokal scores had no impact on OS, PFS and EFS. Five pts progressed to BC (1 myeloid, 4 lymphoid) within the 5 first years and died after allogeneic stem cell transplantation. The PFS rates were 97.5% at 2 years, 92% at 5 years, 88.6% at 10 and 14 years, EFS rates were 76% at 2 years, 60% at 5 years, 45% at 10 years and 21% at 14 years (figure 1), OS rates were 98% at 2 years, 95% at 5 years, 87% at 10 and 14 years.
Figure 1: PFS and EFS in pts on IM first-line. (Dashed lines represent 95%CI).
MR4.5 was achieved in 58 (48.5%) pts after a median of 46 (3-191) months and TFR strategy (or trial) was proposed in 28 pts (23.5%) and successful in 15 (12.5%) pts. At latest follow-up, after a median of 85.5 (4-180) months, 64 (53.5%) pts are still on IM, and 44 (37%) have switched to an alternative therapy for intolerance (17 pts, 14%) or resistance (16 pts, 13.5%, 7 with a BCR-ABL mutation) to IM and 11 for other causes (pregnancy, secondary tumors…). Overall, at latest follow-up, 10/120 pts died, 5 of CML progression and 5 from other causes.
Conclusions
After a very long median follow-up of more than 85 months, IM still consistently provides high rates of remission and survival, without disease progression and severe long-term toxicities. In addition, half of the pts reached the MR4.5 level, ≥2 years stable in 23.5% of the pts offering the possibility of a treatment-free strategy.
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Nicolini: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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria; ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria. Etienne:Novartis: Consultancy, Honoraria; BMS: Honoraria.
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Background & aims
In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), ...combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy.
Methods
In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center all expressed in % on the international scale (IS). All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR).
Results
Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8-52.8) 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. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had "major" BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at "6", and "12" months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI).
The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1.
The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 1.03-1.16), 24 months (p=0.005, OR = 1.08 1.02-1.14) and 48 months (p=0.024, OR = 1.09 1.01-1.17, but not with the mean doses of nilotinib p=0.84, OR = 0.99 0.99-1.01, p=0.087, OR = 1 0.99-1.01, and p=0.88, OR = 1 0.99-1.01 respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke).
Conclusion
Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred. However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress.
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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. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Rea:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria.
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