ALBERT

Description: Abstract 2281 Introduction. Imatinib is the standard of care for CML in early chronic phase. Until now, even in stable complete molecular response, discontinuation of imatinib is not recommended, and imatinib remains a life-saving drug to be taken chronically. Long term side effects, including the incidence of second malignancies, represent a potential relevant issue. Roy et al (Leukemia 2005) reported an unexpected incidence of second neoplasms in patients treated with imatinib after interferon (6/189 patients, 3.2%; urinary tract cancer: 4/6). In contrast, an analysis performed by Novartis Pharma (Pilot et al, Leukemia 2006) on 9518 patients treated with imatinib (including pre-treated patients) did not provided evidence for an increased overall incidence of second malignancies. According to epidemiologic data (Registro Tumori) in Italy, the annual incidence of neoplasms varies from 1%, in the range of age between 50 and 69 years, to 3% for patients over 70 years. AIM. To evaluate the incidence of second malignancies in CML patients treated with imatinib frontline. METHODS. Overall, 559 patients have been enrolled in 3 concurrent clinical studies of the GIMEMA CML Working Party: CML/021, Imatinib 800 mg in intermediate Sokal risk patients (Clin Trials Gov. NCT00514488); CML/022, Imatinib 400 mg vs 800 mg in high Sokal risk patients (Clin Trials Gov. NCT00510926); CML/023, observational, Imatinib 400 mg. We evaluated the incidence of II malignancy notified as severe adverse events reported by the GIMEMA clinical Centers. RESULTS. The median age at the diagnosis of CML was 52 (extr.18 – 84) years; 308 patients (55%) were ≥ 50 years. The median follow-up is currently 60 months. Eighteen patients (3.2%) developed a second malignancy at a median time of 20 months (extremes 2 – 52) from the start of imatinib therapy (Table 1); 4 of these malignancies (2 colon cancer and 2 NHL) were diagnosed within 6 months. All patients were older than 50 years (median 64, extremes 50 – 79) at the diagnosis of the second malignancy. Fifteen out of the 559 (2.7%) patients died due to second neoplasm progression. CONCLUSION. In this multicentre nation-wide experience of CML patients treated with imatinib frontline, the incidence of life-threatening or requiring hospitalization secondary neoplasms (severe adverse events), seems not to be superior to the observed incidence of neoplasm in the Italian national population. In particular, in contrast to what previously reported, no increased incidence of urinary tract cancer was observed. Disclosures: Gugliotta: Novartis: Honoraria. Castagnetti: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Martinelli: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Pane: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Saglio: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baccarani: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Description: Abstract 3412 The phase II explorative study of intermittent Imatinib (IM) treatment (InterIM) in elderly patients with Ph + chronic myeloid Leukemia (CML) who achieved a stable complete cytogenetic response (CCgR) after at least 2-years standard IM therapy (any dose between 300 and 800 mg/day) was started in April 2008 and closed for the enrollment in August 2009, since more than 78 patients required by statistics were included into the study. The main objective of the study was to investigate if after 12 months (trial time) the CCgR achieved with standard (daily administration) IM therapy could be maintained with InterIM. For this purpose, the CgR status was assessed by Interphase Fluorescence In Situ Hybridization (I-FISH) on peripheral blood (≥ 200 cells counted) every 3 months. When I-FISH (% Ph + nuclei) increased more then 1%, chromosome banding analysis (CBA) on bone marrow was performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities (ACA). At the present time, out of the 95 patients who were enrolled, 82 patients were evaluable and out of them 77 (94%), 73 (89%), 71 (87%) and 70 (85%) completed 3, 6, 9 and 12 months of the treatment program, respectively. Therefore, the great majority of patients completed the study core and at the end of 2010 all the patients are expected to complete the trial time (12 mo). During the first 12 months of InterIM, 1% to 11% of the evaluable patients at 3, 6, 9 and 12 months showed an I-FISH 〉1% Ph+ nuclei (Figure 1). Figure 1 Distribution of patients according to I-FISH Figure 1. Distribution of patients according to I-FISH Totally, eleven (13%) out of 82 patients treated with InterIM showed an I-FISH 〉1% and they were checked by CBA on bone marrow (Figure 2). Out of them only 3 cases, that means 4% of the 82 evaluable patients, lost the CCgR and resumed standard IM therapy (daily administration), but none completed 3 months of therapy. All the patients lost the MMR and increased several folds the BCR-ABL transcript levels. Two pts had a low risk Sokal and one a high risk; age was 66, 69, 77 years; time from diagnosis was 29, 91 and 100 months; duration of IM therapy was 29, 83 and 84 months; the IM dose was 400mg in all cases. Figure 2 Cytogenetic and molecular response in 11 cases who showed I-FISH 〉1% + nuclei and who were checked by CBA on bone marrow. Black boxes shows the 3 cases who lost the CCgR Figure 2. Cytogenetic and molecular response in 11 cases who showed I-FISH 〉1% + nuclei and who were checked by CBA on bone marrow. Black boxes shows the 3 cases who lost the CCgR As concern as molecular response, 99% of the patients had a major molecular response (MMR=

Description: In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

Description: Abstract 860 Background: Elderly CML patients treated with Imatinib (IM) in early chronic phase (CP) have similar cytogenetic response and survival compared with younger patients, but they show a lower compliance to standard IM therapy (400 mg/day). Aims: The aim of the study is to investigate if CCgR that has been achieved with standard (daily administration) IM therapy can be maintained with the same dose of IM given intermittently (INTERIM). Methods: The study population is represented by elderly patients (≥ 65 years old) with Ph+ CML and with stable CCgR after at least 2 years of standard IM therapy (daily administration). IM is given at the same dose that was given at the time of enrollment by the following intermittent schedule: 1 week on / 1 week off for the 1st month; 2 weeks on / 2 weeks off for the 2nd and 3rd month; 1 month on / 1 month off from the 4th month thereafter. In cases of loss of CCgR INTERIM was stopped and standard therapy (daily administration) was resumed. After 12 months, the patients who are in continuous CCgR are advised to continue the intermittent study schedule and to be followed indefinitely. The CgR status was evaluated at baseline (by conventional cytogenetics on bone marrow and FISH on peripheral-blood) and every 3 months during the study (only by FISH on peripheral-blood). If FISH (% of Ph+ cells) increased more than 1% in two consecutive examinations, evaluation of marrow cells metaphases was performed to confirm the loss of CCgR and to check for additional cytogenetic abnormalities. Quantitative molecular assessment of BCR-ABL transcript by RQ-PCR on peripheral blood was due at baseline and every 3 months during the study and mutational analysis of ABL was performed in case of loss of CCgR. Results: One-hundred and fourteen patients have been considered eligible, but 17 (15%) refused to enter into the protocol. Out of 97 enrolled patients, 87 started INTERIM, 5 patients (5%) went off the study for major protocol violation before the 3rd month and, at present, 82 patients are ongoing. Of these 82 patients, 52, 30 and 11 completed the 3rd, 6th and 9th month, respectively. The preliminary results of the first 6 months are here reported. The distribution of patients according to FISH results is shown in Fig. 1. Only 1/68 pts (at 6th month) showed an increased 〉1% in Ph+ cells by FISH but he maintained a CCgR when checked by conventional cytogenetic. As showed in Fig. 2, 96 to 87% of patients maintained a major molecular response MMR (≤0,1) according to International Scale (IS). Conclusions: This study is trying to test the minimum effective dose of Imatinib to maintain the CCgR in elderly CML patients with stable CCgR. The preliminary results at 6 months do not show negative trends both for cytogenetic and molecular response. Therefore, the study is ongoing and all patients are expected to complete the trial time (12 months). Disclosures: No relevant conflicts of interest to declare.

Description: BACKGROUND: The INTERIM study (ClinicalTrials.gov NCT 00858806) showed that in elderly (〉 65 years) Ph+ CML patients selected for a stable complete cytogenetic response (CCgR) lasting 〉 2 years, the policy of intermittent imatinib treatment (one month on/one month off) may affect the markers of residual disease (CCgR and major molecular response, MMR or MR3.0), but not the clinical outcomes (overall survival and progression-free survival) (Russo D et al, Blood 2013; 121(26):5138-44). AIMS: To update the results of the INTERIM Study, with a follow up ≥ 5 years. METHODS: After 4 years of follow up, patients continouing INTERIM treatment were monitored with peripheral blood RT-Q-PCR every 3 months according to the ELN-2013 guidelines. RESULTS: At 48thmonth, out of 76 patients enrolled in the INTERIM study, 13 (17%) had lost CCgR and MMR, 14 (18%) had lost MMR only and 50 patients (75%) continued INTERIM. The patients who had lost CCgR and/or MMR resumed imatinib continuously and all of them regained the CCgR and the MMR, within 3 to 12 months. No patient progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. No patient complained of new or more severe side effects during the months “on”. After a follow up ≥ 5 years, 45/76 (59%) enrolled patients are on INTERIM, with a probability of maintaining intermittent administration of 59% (95% CI: 46-69). No patient lost the CCgR and only 9 additional patients lost the MMR while on intermittent treatment. All these patients resumed continuous imatinib treatment and regained the MMR. Thus, at ≥ 5 years, the probability of maintaing CCgR is 80% (95% CI 68-87) and the probability of maintaining the MMR is 61% (95% CI: 48-71). From start of INTERIM, 6 patients died but no deaths were related to CML progression (3 cases of other non haematological neoplasms, 1 stroke, 1 myocardial infarction, 1 chronic obstructive pulmonary disease).The PFS at ≥ 5 years is 94% (95% CI: 89-100) CONCLUSIONS: In summary, with a follow up ≥ 5 years, intermittent imatinib administration (INTERIM) confirmed to be safe, to produce a reversible increase of residual molecular disease in about one third of patients, but not to affect the long-term outcome. Aknowledgments: This work was supported in part by EuropeanLeukemiaNet (contract LSHC-CT-2004-503216) through the European Treatment and Outcome Study (EUTOS), supported by Novartis Oncology Europe, and COFIN 2009 Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; Bristol-Meyers and Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Soverini:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Rosti:Consultant: Consultancy, Speakers Bureau; Bristol-Meiers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

Description: Abstract 1682 Background: The introduction of Imatinib has significantly improved the outcome for patients with Ph+ CML. The complete cytogenetic response (CCgR) is a strong and confirmed predictor of improved long-term outcome. According to current recommendations, Imatinib (IM) should be continued indefinitely. However, optimal responders can be eligible for investigational trials of treatment discontinuation. AIMS: This study (ClinicalTrials.gov NCT 00858806) describes the effects of a policy of intermittent Imatinib (INTERIM) treatment (one month on/one month off) on cytogenetic and molecular responses in a selected population of patients ≥ 65 years old who were receiving treatment with Imatinib for 〉 2 years and were in stable complete cytogenetic response (CCgR). The primary endpoint of the study was the proportion of patients who maintained CCgR after 1 year of INTERIM. The secondary endpoint was the level of BCR-ABL transcripts during INTERIM METHODS: Cytogenetic and molecular responses were monitored by FISH and RT-Q-PCR every 3 months. The definition of CCgR, and of CCgR loss was based on CBA of marrow metaphases which was performed at baseline and in all the patients who became FISH positive (BCR-ABL–positive nuclei 〉 1%). Major molecular response (MMR), corresponding to a 3-log reduction in BCR-ABL transcript level from the standardized baseline, was defined as BCR-ABL ≤0.1%IS and was indicated as MR3.0. For the purposes of this study, complete molecular response (CMR) was defined as a 4-log reduction in BCR-ABL transcript level ( 1%), with the exception of the duration of imatinib therapy (HR = 0.23, 95% CI 0.008–0.73, P =.01). Among patients with prior Imatinib treatment longer or shorter than 48 months, the probability of maintaining FISH negativity was 94% (95% CI 88–100%) vs 71% (95% CI 53–89%), respectively, HR = 0.23 (P =.007). All the 6 patients who lost CCgR regained the CCgR with daily Imatinib, at the same dose, defined by FISH negativity after 3 to 9 months (4/6 also CBA negative, 2 patients refused bone marrow aspiration). At baseline, all but one patient (99%) were in MMR (MR3.0, BCR-ABL ≤0.1%IS), and 63 patients (83%) were in MR4.0 (