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In: Blood Cancer Journal, Springer Science and Business Media LLC, Vol. 10, No. 6 ( 2020-06-08)

Type of Medium: Online Resource

ISSN: 2044-5385

URL: Article

DOI: 10.1038/s41408-020-0333-2

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2600560-8

In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 7 ( 2021-07), p. 2102-2107

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-01098-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. 136, No. Supplement 1 ( 2020-11-5), p. 8-9

Abstract: Introduction. New guidelines for the management of dyslipidemia and lipid modification in order to reduce the risk of cardiovascular (CV) events have been recently published by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). New recommendations regarding the target value of plasma lipids in very high and high CV risk patients have been provided, in addition to an estimate of the CV risk with a new Systematic Coronary Risk Evaluation (SCORE) chart. Few data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib, and the association with arterial occlusive events (AOEs). We therefore analyzed a large real-life cohort of Italian patients with CML treated with nilotinib outside of clinical trials and evaluated the association between AOEs and plasma lipoproteins levels; moreover, we estimated the prognostic value of the new SCORE chart to predict AOEs. The secondary endpoint was to report the management of dyslipidemia in the clinical practice. Methods. We identified 233 adult patients with CML who were treated in 20 Italian centers with nilotinib. All patients were stratified into low to moderate (SCORE ≤ 5%) or high to very high (SCORE risk & gt;5%) CV risk, according to the new version of the SCORE 2019. We recorded concentration levels of cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL) and triglycerides at diagnosis of CML, before starting ponatinib and therefore after 3, 6 and 12 months of treatment. All AOEs (cerebrovascular, peripheral vascular and CV events excluding hypertension) were considered. Results. The median age was 50 years (range 20-88) and the Sokal score was intermediate-high in 45.5% of patients. The median follow-up was 5 years (range 3.4-10.5). Nilotinib was administered as first line of therapy in (72%) of cases or second or subsequent lines of treatment for inefficacy (20.9%) or intolerance (7.1%). At baseline, nilotinib was administered at the following doses: 800 mg/day in 9.3% of patients, 600 mg/day in 87% of patients, 400 mg/day in 3.1% of patients and 300mg in 0.6% of patients, respectively. The median time of drug exposure was 60 months (range 2-155). The 48-month cumulative incidence rate of AOEs was 14.1±2.7%. Patients with cholesterol plasma levels & gt; 200 mg/dL and LDL & gt;70 mg/dL at baseline and 3 months after starting nilotinib, showed a significantly higher incidence of AOEs (24.5±7.3% vs 11±2.7%, P=0.02 and 22.3±4.9% vs 5.9±2.6, P=0.003, respectively) Figure 1. Patients with triglycerides levels & gt; 200 mg/dL 3 months after starting nilotinib, showed a significantly higher incidence of AOEs (56±20.5% vs 13.3±2.7%, P=0.011) Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (32.8.1±9% vs. 9±1%±2.6%, p=0.001). In multivariate analysis, statistical significance of cholesterol plasma levels & gt; 200 mg/dL and LDL & gt;70 mg/dL after 3 months and high-very-high SCORE was maintained (P=0.018, HR=3.4, 95% CI=1.2-9.4 and P=0.004, HR=3.5, 95% CI=1.5-8.2, respectively). Overall, 46 patients (20.5%) presented dyslipidemia at CML diagnosis and 65 (29%) at the start of treatment with nilotinib. Despite dyslipidemia, only 6 patients were taking statins during the treatment with nilotinib and only 5 started it after 3 months of nilotinib: 3 patients were treated with rosuvastatin and 2 with pravastatin. Conclusions. Our findings suggest that a proper control of dyslipidemia, keeping cholesterol and triglycerides plasma levels ≤ 200 mg/dL and LDL ≤70 mg/dL is associated with reduced risk of AOEs in CML patients treated with nilotinib. An under estimation of the clinical importance of elevated plasma lipids as a risk factor for AOEs events represents a possible issue in the real-life. Figure 1 Disclosures Abruzzese: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Galimberti:Incyte: Honoraria; Novartis: Speakers Bureau. Castagnetti:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Gugliotta:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: 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-2020-134496

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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. 2792-2792

Abstract: Background: The European LeukemiaNet (ELN) response criteria are widely used to decide, at given time points, when the treatment with tyrosine-kinase inhibitors (TKIs) of CML patients should be continued (optimal response, OR), when a careful monitoring is required (warning, W) or when the therapy should be changed (failure, F). The 2013 ELN response criteria are the same for all chronic phase CML patients, irrespective of the prescribed TKI, but the time to response is influenced by the first-line TKI. Despite faster responses, a clear survival advantage of 2nd generation TKIs over imatinib (IM) has not been demonstrated yet. A validation of the 2013 ELN response definitions and an analysis of their prognostic impact in IM-treated patients may provide important information. Aims: The aim of our study was to assess the significance of 2013 ELN response criteria in CML patients treated frontline with IM, investigating whether or not optimal responders, warnings or failures at 3, at 6 and at 12 months have a different long-term outcome. Methods: 559 patients enrolled within 3 prospective clinical trials (NCT00514488, NCT00510926, observational trial CML/023) were analyzed (ITT population of each study). The 3-month response according to 2013 ELN criteria was not fully evaluable due to missing cytogenetic analysis in 452/559 patients, so we focused on the early molecular response (EMR, BCR-ABL 〈 10% at 3 months), corresponding to OR. The responses at 6 and 12 months were retrospectively defined according to 2013 ELN criteria: F, BCR-ABL 〉 10% and/or Ph+ 〉 35% at 6 months, BCR-ABL 〉 1% and/or Ph+ 〉 0 at 12 months; OR, BCR-ABL 〈 1% and/or Ph+ 0 at 6 months, BCR-ABL 〈 0.1% at 12 months; W: intermediate conditions. As the ELN criteria changed over time, not all the failures switched to alternative treatment. Progression: transformation to advanced phases (2013 ELN definitions) at any time, including after treatment discontinuation. Overall survival (OS): all the deaths at any time (in-study or off-study) were included. Leukemia-unrelated death: known cause of death, no progression, CCyR and/or MMR 〈 6 months prior to death; all other deaths were classified as leukemia-related (LRD). The cumulative incidence of LRD was estimated considering the competing risk of leukemia-unrelated death. Results: The median follow-up was 76 months (66-99 months). The patients with OR at 3 months were 82%; the patients with OR-W-F at 6 months were 76%, 14% and 10%, respectively; the patients with OR-W-F at 12 months were 65%, 20% and 14%, respectively. The OS, the progression-free survival (PFS) and the cumulative incidence of LRD according to the presence-absence of EMR were 87-81% (p=0.015), 85-81% (p=0.035) and 11-5% (p=0.019), respectively. Combining the Sokal score and the EMR, the patients were divided into 4 groups, low and intermediate risk/responders, low and intermediate risk/not responders, high risk/responders, high risk/not responders: the OS and the cumulative incidence of LRD across the 4 groups were 88%, 84%, 86% and 70% (p=0.005, Figure 1) and 3%, 9%, 10% and 20% (p 〈 0.001), respectively. The OS according to the 6-month ELN response (OR-W-F) was 88%, 88% and 70% (p 〈 0.001, Figure 2), the PFS was 88%, 86% and 64% (p 〈 0.001), while the cumulative incidence of LRD was 2%, 5% and 28% (p 〈 0.001), respectively. The patients subsequently remaining on IM treatment according to the ELN response at 6 months (OR-W-F) were 77%, 52% and 26%, respectively. The OS, the PFS and the cumulative incidence of LRD according to ELN response criteria at 12 months (OR-W-F) were 89%, 93% and 78% (p 〈 0.001, Figure 3), 89%, 93% and 77% (p 〈 0.001), and 1%, 1% and 16% (p 〈 0.001), respectively. The patients subsequently remaining on IM according to the response at 12 months (OR-W-F) were 80%, 72% and 35%, respectively. Conclusions: The patients without OR at 3 months (particularly high Sokal score patients) had a significantly poorer outcome compared to patients with OR. The warnings at 6 and 12 months had a similar outcome to optimal responders at the same time points; both had a significantly better outcome than the failures. Compared to optimal responders, a larger proportion of patients classified as warnings was subsequently switched to alternative treatment; the subsequent treatment may explain, at least in part, the absence of outcome differences between these 2 groups. Disclosures Castagnetti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Gugliotta:BMS: Honoraria; Novartis: Honoraria. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau. Soverini:Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Cavo:Jansenn: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Honoraria; Millenium Pharmaceuticals: Honoraria; Onyx: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Martinelli:MSD: Consultancy; Roche: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy. Baccarani:BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; Pfizer: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; ARAID Pharmaceutical Inc.: Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Other: Travel, Accommodations, Expenses; BMS: Other: Travel, Accommodations, Expenses; Pfizer: Other: Travel, Accommodations, Expenses; ARIAD Pharmaceutical Inc.: Other: Travel, Accommodations, Expenses. Rosti:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.2792.2792

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. 122, No. 21 ( 2013-11-15), p. 1486-1486

Abstract: The e13a2 and the e14a2 are the most frequent BCR-ABL1 transcripts in chronic myeloid leukemia (CML) patients. The aim of the present study was to assess the prognostic value of the e13a2 (b2a2) or the e14a2 (b3a2) fusion transcripts on the long-term outcome of early chronic phase (ECP) CML patients treated frontline with imatinib mesylate (IM). Few studies, mostly based on a small number of patients or with a relatively short observation, have been published, particularly in ECP setting. Due to partially conflicting data, the transcript type is not actually considered an established baseline prognostic factor. To our knowledge, this is the first long-term analysis conducted in the context of large prospective studies. Methods A retrospective analysis of 3 GIMEMA CML WP prospective clinical studies (NCT00514488, NCT00510926, observational study CML/023) was performed. All the 559 enrolled patients were analyzed. A qualitative RT-PCR for BCR-ABL1 transcript was routinely performed at enrollment. Patients expressing rare transcripts or with both e13a2-e14a2 transcripts were excluded: 493 out of 559 patients were included, 203 (41%) with e13a2 transcript and 290 with e14a2 transcript (59%). Definitions. Major molecular response (MMR): BCR-ABL1IS ratio 〈 0.1%. Deep molecular response (MR4.0): detectable disease ≤ 0.01% BCR-ABL1IS or undetectable disease with ≥10,000 ABL1 transcripts. Progression: transformation to accelerated or blastic phase. Failure: according to 2013 ELN recommendations. Event: failure or permanent discontinuation for any reasons. All the deaths, at any time and for any reasons, were included. Results The median follow-up was 76 months; 95% of the patients had at least a 5-year observation. The 2 groups were comparable for demographic and hematologic characteristics, except for the proportion of male patients, that was higher in the e13a2 group (p = 0.05), and for the baseline percentages of eosinophils, that was lower in the e13a2 group (p = 0.009). The Sokal, Hasford and EUTOS risk score distributions and the proportion of patients with CCA in Ph+ cells were comparable. The complete cytogenetic response (CCyR) rate at 12 month was not significantly different (75% and 79% in e13a2 e14a2 patients, respectively, p=0.274), but the MMR rate at 18 months and the MR4.0 at 36 months were significantly lower in e13a2 patients (52% and 67%, p = 0.001; 20% and 30%, p = 0.013, respectively). As far as the rapidity of response, the time to MMR and the time to MR4 were significantly slower for patients with e13a2 transcript (12 and 6 months; 54 and 37 months, respectively), with an inferior overall estimated probability of MMR (85% and 92%, p 〈 0.001) and MR4 (57% and 71%, p = 0.002). The overall survival (83% and 86%, p = 0.023), the progression-free survival (81% and 86%, p = 0.007), the failure-free survival (54% and 71%, p 〈 0.001) and the event-free survival (46% and 61%, p = 0.003) were significantly lower in patients with e13a2 transcript (figure 1). In a multivariate analysis (Cox model), the transcript type retained its prognostic significance, when adjusted for other relevant variables. Analyzing separately the patients treated with IM 400 mg (n = 371; e13a2 and e14a2 transcript: 208 and 163 patients, respectively) or IM 800 mg (n = 122; e13a2 and e14a2 transcript: 82 and 40 patients, respectively), all the above mentioned response and outcome differences were confirmed, with one exception: in the high-dose IM group the overall survival probability was inferior for the e13a2 patients, but, probably due to the small number of patients, the difference was not statistically significant (83% and 86%, p = 0.268). Conclusions A long-term analysis in a large cohort of CML patients suggests that the e13a2 transcript is an adverse prognostic factor in ECP CML patients treated frontline with IM. An independent evaluation is required for confirmation. Acknowledgments University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures: Castagnetti: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:BMS, Novartis: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1486.1486

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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. 2279-2279

Abstract: Abstract 2279 Over the years, Bcr-Abl kinase domain (KD) mutation analysis has been more and more extensively applied in Philadelphia-positive (Ph+) patients (pts) resistant to tyrosine kinase inhibitors (TKIs) to assist clinicians in therapeutic decisions. We reviewed the database recording the results of mutation analyses performed in our laboratory from January 2004 to June 2010. Overall, 2996 Bcr-Abl KD mutation screening tests were successfully performed by denaturing-high performance liquid chromatography (D-HPLC) and/or direct sequencing of the Bcr-Abl KD (residues 206–524). The total pts analyzed were 1139 (CML, n=1005; Ph+ ALL, n=134); the number of tests per patient ranged from 1 to 14. One hundred and ninety-one tests on 148 pts were performed in 2004, 391 tests on 214 pts in 2005, 469 tests on 217 pts in 2006, 521 tests on 241 in 2007, 536 tests on 301 pts in 2008 and 576 tests on 311pts in 2009. Overall, 869/2996 tests (29%) yielded a positive result. In 91/869 (10.5%) cases, D-HPLC showed evidence of sequence variations below the lower detection limit of sequencing; in the remaining 778 cases mutations could be characterized – a single mutation was detected in 646 (83%) cases, 2 mutations in 95 (12%) cases, 3 mutations in 25 (3%) cases, 4 or more mutations in 12 (2%) cases. In those pts for whom a longitudinal analysis was performed, 2 or more mutations accumulated as a consequence of multiple lines of therapy in 69% of cases, while in the remaining cases they concomitantly emerged under the same TKI. In 8 (10%) cases, small insertions or deletions were detected (Δ248-274 in 4 cases). Silent mutations were detected in 32 cases, either alone (11 cases) or in association with missense mutations. The K247R polymorphism was detected in 3 pts only. Five hundred and seventy-seven pts were analyzed at the time of resistance to imatinib (IM), 94 at the time of resistance to a 2nd TKI, 34 at the time of resistance to a 3rd TKI. In the IM-resistant setting, the ten most frequently detected mutations were F359V (13.4% of pts), M351T (12.3%), M244V (12.3%), H396R (10.3%), G250E (8.2%), E355G/D (8.2%), E255K/V (6.1%), Y253F/H (6.1%), T315I (4.1%), F317L (4.1%) in chronic phase (CP) CML pts; T315I (15.6%), G250E (13.7%), M351T (9.8%), E255K (7.8%), Y253F/H (7.8%), M244V (7.8%), Q252R/H (5.8%), H396R/P (5.8%), L384M (3.9%), F359V (3.9%) in myeloid blast crisis (BC) CML pts; and E255K/V (16.6%), T315I (16.6%), Y253F/H (15.2%), G250E (12.5%), M244V (8.3%), Q252R/H (5.5%), M351T (4.1%), L248V (2.7%), F359V (2.7%), D276G (2.7%) in lymphoid BC CML/Ph+ ALL pts. In the CP CML setting, 102 pts were analyzed because of strictly defined failure to 1st-line IM according to the 2006 ELN recommendations. Thirty-two (31%) were positive for mutations; only one had a T315I. Ninety-nine out of 128 (77%) CML and Ph+ ALL pts who were reported to be resistant to a 2nd or a 3rd TKI (either nilotinib or dasatinib) were positive for one or more mutations. The ten most frequent ones were T315I (30.3% of pts), F317L (16.2%), Y253H (16.2%), F359V (7.1%), V299L (7.1%), E255K (6.1%), E255V (5.1%), F359I (4%), T315A (3%), F359C (2%) – either alone (56% of pts), combined (29%), or together with other mutations (15%). Preferential associations between mutations were observed. Eighty-five CP CML pts on IM were analyzed because of increasing Bcr-Abl transcript levels, including 61 pts who experienced ≥1-log increase without loss of major molecular response (MMR) and 24 pts who experienced ≥1-log increase leading to loss of MMR (but not of complete cytogenetic response). Mutations were identified in 2/61 (3%) and 3/24 (12.5%) pts, respectively. Forty-four CP CML pts (Low Sokal, n=14; Intermediate Sokal, n=15; High Sokal, n=15) were screened for mutations at the time of diagnosis, including 21 pts who later relapsed with evidence of mutations. Only 1 High Sokal risk patient scored positive for a mutation at diagnosis (Y342C); at the time of relapse, however, the mutation had disappeared and an M244V was instead detectable. Fifty-five Ph+ ALL pts were analyzed at the time of diagnosis. D-HPLC showed evidence of mutations in 3 (5%) pts, but they were all below the lower detection limit of sequencing. All 3 pts later relapsed with KD mutations (T315I). Additional sub-analyses will be presented. Our seven-year experience in a large series of pts sheds further light on the frequency and clinical relevance of Bcr-Abl KD mutations in the IM and in the 2nd generation TKI era. Supported by ELN, AIL and PRIN. Disclosures: Rosti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Baccarani: NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Martinelli: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2279.2279

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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. 1598-1598

Abstract: In the current clinical practice, imatinib is widely used also in very elderly patients with chronic myeloid leukemia (CML) at different doses based on concomitant diseases and physician' judgment. However, data on long-term follow-up of these patients are still lacking. To address this issue, we revised in our retrospective database 233 CML patients aged ≥ 75 years and treated with imatinib frontline in 34 italian hematological centers from 2/2002 to 7/2014. Median age at diagnosis was 78.4 years [interquartile range (IQR) 76.3 - 81.3], there were 113 males (48.5%) and 120 females (51.5%), median WBC, Hb and PLT counts were 45.0 x 109/l (IQR 29.4 - 83.4), 12,4 g/dl (IQR 11.0 - 13.6) and 375 x 109/l (IQR 238 - 680), respectively. Sokal Risk at diagnosis was low in 1 patient (0.4%), intermediate in 149 (67.4%), high in 71 (32.2%) and not evaluable in 12. One or more concomitant diseases requiring specific treatments were present in 225/233 patients (96.5%). Median interval from diagnosis to imatinib start was 0.7 month (IQR 0.2 - 1.4): the initial imatinib dose was 400 mg/day in 161 patients (69.1%), 300 mg/day in 57 (24.5%) and 〈 300 mg/day in 15 (6.4%). According to WHO, a grade 3 - 4 hematological and extra-hematological toxicity was reported in 44 (18.8%) and 41 (17.6%) patients, respectively. As to cumulative response, 13 patients (5.6%) discontinued IM due to early toxicity, 4 (1.7%) were resistant and 2 (0.8%) died from unrelated cause early after IM initiation: the remaining 214 patients (91.9%) achieved a complete haematological response (CHR). Among these 214 patients in CHR, 13 refused any other karyotipic or molecular evaluation, 23 achieved CHR only and 178 (76.4% of all 233 patients) achieved a cytogenetic response (CyR), which was partial in 16 patients and complete (CCyR) in 162 (69.5% of all 233 patients). In addition, among the 162 patients in CCyR, 125 (53.6% of all 233 patients) achieved a molecular response (MolR) (ratio 〈 0.1). A blastic phase occurred in 11 patients (4.7%). After a median follow-up from imatinib start of 45.0 months (IQR 22.3 - 72.0), 70 patients have died (9 from disease progression and 61 from unrelated causes), 16 patients were lost to follow-up and 147 are still alive (115 of them still in treatment with imatinib): 5-year event-free survival (EFS) and overall survival (OS) were 51.4% (CI95% 43.9 - 58.9) and 68.5% (CI95% 61.2 - 75.8), respectively. At univariate analysis, only the initial dose of imatinib (400 vs ≤ 300, p=0.03) was a significant predictive factor for CCyR achievement while only PLT count ≤ 500 x 109/l (p=0.031) was a significant predictive factor for MolR achievement. At multivariate analysis for EFS, achievement of a MolR (OR 0.25, 95%CI 0.14 - 0.43, p 〈 0.001), achievement of a CCyR (OR 0.40, 95%CI 0.23 - 0.67, p=0.001) and spleen enlargement (OR 1.56, 95%CI 1.01 - 2.41, p=0.042) were independent prognostic factors; at multivariate analysis for OS, achievement of a MolR (OR 0.30, 95%CI 0.18 - 0.49, p 〈 0.001), age 〈 80 yrs (OR 0.53, 95%CI 0.33 - 0.86, p=0.011) and male gender (OR 1.80, 95%CI 1.11 - 2.91, p=0.016) were independent prognostic factors. In conclusion, the long term follow-up of very elderly CML patients who started imatinib is very good and justify any effort to treat these patients with standard doses, in order to achieve cytogenetic and molecular responses as in younger subjects. Disclosures Castagnetti: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Gugliotta:BMS: Honoraria; Novartis: Honoraria. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1598.1598

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. 126, No. 23 ( 2015-12-03), p. 1582-1582

Abstract: Tyrosine-kinase inhibitors (TKIs)have completely changed the expected survival of chronic myeloid leukemia (CML) patients which is now approaching that of the general population: a relevant proportion of CML patients are currently elderly or very elderly. Very elderly patients represent generally a small proportion in published experiences. Older CML patients imatinib treated, as it happens in the general population, receive other drug treatments for associated chronic illnesses. Our aim is to assess if and which classes of concomitant drugs have an impact on cytogenetic response in chronic phase (CP)-CML very elderly (age 〉 75 years) patients. Two hundred and twelve very elderly CP-CML patients, imatinib treated at 33 italian hematological institutions have been retrospectively evaluated. Median age at diagnosis was 78.5 years (range 75.0-93.0); 111 (52.4%) were male. Sixty-two (29.2%) were Sokal high risk. Sixty-seven (31.8%) were treated with reduced dose imatinib ( 〈 400 mg/day), and the remaining patients with imatinib 〉 400 mg/day. Concomitant drugs were 1-2 in 73 (34.4%) patients, 3-4 in 59 (27.8%), and 〉 5 in 64 (30.2%); 16 (7.6%) did not assume any concomitant drug. Drugs more frequently used were antiplatelets, assumed by 104 (49.1%) patients, followed by diuretics in 91 (42.9%) patients, proton pump inhibitors (PPIs) in 86 (40.6%), ACE inhibitors in 55 (25.9%), beta blockers in 44 (20.7%), angiotensin II receptors blockers (ARB) in 41 (19.3%), calcium channel blockers in 34 (16%), statins in 25 (11.8%), and alpha blockers in 11 (5.2%). Univariate logistic regression models were computed to assess the association between cytogenetic response after 6 or 12 months of imatinib treatment and number of concomitant drugs or selected drug classes. Statistical analyses were done using JMP 11.1 (SAS Institute Inc., Cary, NC, USA). Complete cytogenetic response (CCyR) was obtained in 124 (58.8%) patients, of whom 70 (33%) within 6 months. Consequently, we focused our study on the impact of number and types of drugs on CCyR rate, which represents the primary therapeutic endpoint in the elderly. Cytogenetic response distribution according to concomitant drugs is reported in table 1. We did not find any significant correlation between number of concomitant drugs, single classes of antihypertensive drugs, antiplatelets, PPIs or statins and CCyR rate at 6 or 12 months. Even though few pharmacokinetic interactions are reported between imatinib and some of medications we considered, this does not seem to have an impact on cytogenetic response rate in our cohort. Indeed, our results confirm the well-known safety and efficacy of imatinib also in very elderly CML patients. Table 1. Cytogenetic response according to concomitant drugs Drug classes Cytogenetic response CCyR 〈 6 months CCyR 7-12 months CCyR 〉 12 months No CCyR Antiplatelets (n=104) 38 (36.5%) 31 (29.8%) 11 (10.6%) 24 (23.1%) Diuretics (n=91) 32 (35.2%) 21 (23.1%) 13 (14.3%) 25 (27.4%) Proton pump inhibitors (n=86) 30 (34.9%) 22 (25.6%) 13 (15.1%) 21 (24.4%) ACE inhibitors (n=55) 19 (34.6%) 11 (20%) 12 (21.8%) 13 (23.6%) Beta blockers (n=44) 18 (40.9%) 11 (25%) 3 (6.8%) 12 (27.3%) Angiotensin II receptor blockers (n=41) 19 (46.3%) 11 (26.8%) 5 (12.3%) 6 (14.6%) Calcium channel blockers (n=34) 10 (29.4%) 7 (20.6%) 6 (17.7%) 11 (32.3%) Statins (n=25) 9 (36%) 7 (28%) 2 (8%) 7 (28%) Alpha blockers (n=11) 4 (36.4%) / 1 (9.1%) 6 (54.5%) Disclosures Castagnetti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy. Tiribelli:Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1582.1582

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. 2196-2196

Abstract: Abstract 2196 Poster Board II-173 BACKGROUND: Imatinib (IM) 400 mg daily is the standard treatment for Chronic Myeloid Leukemia (CML) in early chronic phase (ECP). The European LeukemiaNet (ELN) recommendations were designed to help identify ECP CML patients responding poorly to front-line IM, suggesting, at given time points, when the treatment strategy should be changed (”failure”), or when “the long-term outcome of the treatment would not likely be as favourable” (“suboptimal response”). Suboptimal response is a “grey zone”: the patient may still have substantial benefit from continuing IM, but other therapies should be considered. AIM: To assess the outcome of “failure” and “suboptimal responders” Philadelphia-positive (Ph+) CML patients in a large multicentric, nationwide experience. METHODS: Between January 2004 and April 2007, 559 patients were enrolled in an observational study and in 2 independent intervention studies of the GIMEMA CML WP (Clin Trials Gov. NCT00514488 and NCT00510926). Response monitoring was based on conventional cytogenetic examination of bone marrow cell metaphases every 6 months and RT Q-PCR evaluations of blood cells after 3, 6, 12 months, and every 6 months thereafter. Definitions: major molecular response (MMR): BCR-ABL/ABL ratio 〈 0,1%IS; failure (according to ELN criteria): no hematologic response (HR) at 3 months, no complete HR (CHR) at 6 months, no cytogenetic response (CgR) at 6 months, no partial CgR (PCgR) at 1 year, no complete CgR (CCgR) at 18 months, loss CHR or CCgR, progression or death; suboptimal response (according to ELN criteria): no CHR at 3 months, no PCgR at 6 months, no CCgR at 12 months, no MMR at 18 months ; optimal response: non-suboptimal and non-failure at each time-point; event: failure or treatment discontinuation for any reason. All the calculations have been made according to the intention-to-treat principle. RESULTS: The patients who fitted the ELN criteria for failure had a significantly lower probability of subsequently achieving a CCgR and a MMR, and had a significantly lower overall survival (OS), failure-free survival (FFS) and event-free survival (EFS). The patients who fitted the ELN definitions of suboptimal response at 6 months (data not shown) and at 12 months (figure 1) had a significantly lower probability than “optimal” responders of subsequently achieving a CCgR and a MMR, and a significantly poorer FFS and EFS (figure 1), while the OS was not different in the two groups (90% and 95%, p= 0.35). CONCLUSIONS Our data confirms that suboptimal responders at 6 and at 12 months have a poorer outcome with respect to “optimal” responders, comparable to the outcome of failure patients. Acknowledgments: European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2196.2196

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. 4532-4532

Abstract: Background: In the ENESTnd trial, nilotinib (NIL) showed a superior efficacy to imatinib (IM) with higher response rates and less frequent progression to advanced phases (ABP). Based on these results, NIL has been approved for frontline treatment of chronic myeloid leukemia (CML). The treatment-free remission (TFR) is actually considered one of the most important treatment goals in CML and a sustained deep molecular response (DMR, MR4 or better) is a pre-requisite to achieve TFR. The 5-year update from the ENESTnd trial showed a superiority of NIL over IM in terms of both MR4 and MR4.5, but differences concerning the stability of DMR have not been reported. Moreover, a significant improvement in the long-term outcome has not been demonstrated yet. Despite the efficacy, cost and safety concerns may limit the NIL use as first line treatment in CML. Independent studies are extremely relevant to confirm or to extend the results of company-sponsored trials. Aims and Methods: To assess the efficacy of NIL frontline in terms of DMR, a phase 3b study was conducted by the GIMEMA CML WP (CML0811; NCT01535391). The primary endpoint was the rate of MR4 at 24 months. Key secondary objectives: evaluation of the kinetics of molecular response, assessment of the safety profile, analysis of the outcome. The starting NIL dose was 300 mg BID, with dose escalation to 400 mg BID in case of suboptimal response or failure according to ELN 2009 criteria, with the exception of progression to ABP and in absence of safety issues or BCR-ABL mutations insensitive to NIL. The molecular response was assessed in GIMEMA standardized molecular laboratories (LabNet network) and the results were expressed according to the International Scale. The MR4 was defined as either detectable disease ≤ 0.01% BCR-ABL or undetectable disease with ≥ 10.000 ABL copies; the MR4.5 was defined as either detectable disease ≤ 0.0032% BCR-ABL or undetectable disease with ≥ 32.000 ABL copies. Sustained MR4 or MR4.5: MR4 or MR4.5 for at least 1 year a, with at least 3 evaluable analysis. Adverse events were recorded continuously. A prospective evaluation of glucose metabolism and serum lipids was planned. All the analysis were performed according to the ITT principle. Results: 130 CML patients in early chronic phase have been enrolled in 32 italian hematologic centers; median age, 50 years (range 18-85); high risk patients, 22%, 6% and 8% according to Sokal, Euro and EUTOS scores, respectively; clonal chromosomal abnormalities in Ph+ cells at baseline, 5%; e13a2 BCR-ABL transcript, 34%. The median follow-up is actually 21 months (all patients had at least 18 months observation; a minimum observation of 24 months will be reached by October 2014). Data with at least 24 months follow-up will be presented on site. At the last contact, the patients still on treatment with NIL were 110/130, 85% (74% with 600 mg, 7% with 300 mg or less, 4% with 800 mg daily), while 20/130 patients, 15%, permanently interrupted the study drug for the following reasons: 3% progression to ABP, 2% failure or suboptimal response (dose escalation not feasible), 1% allogeneic stem cell transplantation, 5% toxicity, 4% other reasons (including consent withdrawal and pregnancy). The complete cytogenetic response rate and the major molecular response rate at 12 months were 76% and 53%, respectively. The rates of MR4 at 3, 6, 12 and 18 months were 2%, 12%, 27% and 29%, respectively. Fifty-four patients achieved a MR4 at least once; the patients with a sustained MR4 were 18/54 (33%, or 14% of the total). The rates of MR4.5 at 3, 6, 12 and 18 months were 0, 3%, 10% and 13%, respectively. Only 3 patients achieved a sustained MR4.5. A significant increase of glycosylated hemoglobin was not observed. The total cholesterol, and both LDL and HDL cholesterol fractions significantly increased during treatment. Triglyceride concentrations had not significant variations. Six patients (5%) had a cardiovascular event, including myocardial infarction and arterial thrombosis. All the patients are still alive. Conclusions: The molecular response rates seem to be superior to the historical data of IM. NIL 300 mg BID as frontline treatment of BCR-ABL+ CML, with dose optimization in case of non optimal response, may improve the proportion of patients able to discontinue TKI treatment. Due to the metabolic effects, a baseline selection is crucial to maximize the therapeutic benefit and to minimize the cardiovascular risks. Disclosures Castagnetti: Pfizer: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Novartis Farma: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rossi:NOVARTIS: Consultancy, Speakers Bureau; BRISTOL MYERS-SQUIBB: Consultancy, Speakers Bureau; ARIAD: Consultancy; ROCHE: Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Soverini:NOVARTIS: Consultancy; BRISTOL MYERS: Consultancy; ARIAD: Consultancy. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Millenium Pharm: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Onyx: Honoraria. Martinelli:Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other. Baccarani:ARIAD: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Rosti:ROCHE: Speakers Bureau; ARIAD: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.4532.4532

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7