Imatinib Duration Research Articles

ENESTgoal Treatment-Free Remission Study: Updated Preliminary Results and Digital Polymerase Chain Reaction Analysis in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Switched from Imatinib to Nilotinib

ENESTgoal Treatment-Free Remission Study: Updated Preliminary Results and Digital Polymerase Chain Reaction Analysis in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Switched from Imatinib to Nilotinib

338P Association of kynurenine, tryptophan and key enzymes involved in kynurenine pathway of tryptophan catabolism with Imatinib duration in patients with chronic myeloid leukemia

338P Association of kynurenine, tryptophan and key enzymes involved in kynurenine pathway of tryptophan catabolism with Imatinib duration in patients with chronic myeloid leukemia

338P Association of kynurenine, tryptophan and key enzymes involved in kynurenine pathway of tryptophan catabolism with Imatinib duration in patients with chronic myeloid leukemia

338P Association of kynurenine, tryptophan and key enzymes involved in kynurenine pathway of tryptophan catabolism with Imatinib duration in patients with chronic myeloid leukemia

Comprehensive Evaluation of Adherence to Therapy, Its Associations, and Its Implications in Patients With Chronic Myeloid Leukemia Receiving Imatinib.

Adherence to oral therapy over a long period is important for optimal outcomes in chronic myeloid leukemia (CML). Patients in the chronic phase of CML (taking imatinib for ≥ 6 months) were assessed by the 8-item Morisky Medication Adherence Scale and European Organisation for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire (C30 and CML 24). Patients were classified as adherent (score 8) and nonadherent (score ≤ 7) as per the 8-item Morisky Medication Adherence Scale. Among 221 patients (male to female ratio = 133:88; median age, 39 (18-65) years; median duration of imatinib, 4 years), the nonadherence rate was 55%(N = 122/221). None of the demographic parameters, including occupation, education status, income, and availability of caregiver, were associated with nonadherence. QoL scores, especially the symptom scores associated with side effects of imatinib, significantly differed between adherent and nonadherent patients. Multivariate analysis revealed global health status as the sole predictor of adherent behavior (odds ratio, 0.978; 95% confidence interval, 0.963-0.994; P = .007). A higher proportion of adherent patients achieved deeper molecular responses. Low QoL was associated with nonadherence to imatinib in patients with CML. It is likely that increased long-term symptom burden due to side effects of imatinib could contribute to nonadherence. Interventions targeting individual components of QoL may improve adherence and outcomes in CML.

Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study.

The aim of the Korean Imatinib Discontinuation Study was to identify predictors for safe and successful imatinib discontinuation. A total of 90 patients with a follow-up of ≥12 months were analyzed. After a median follow-up of 26.6 months after imatinib discontinuation, 37 patients lost the major molecular response. The probability of sustained major molecular response at 12 months and 24 months was 62.2% and 58.5%, respectively. All 37 patients who lost major molecular response were retreated with imatinib therapy for a median of 16.9 months, and all achieved major molecular response again at a median of 3.9 months after resuming imatinib therapy. We observed newly developed or worsened musculoskeletal pain and pruritus in 27 (30%) patients after imatinib discontinuation. Imatinib withdrawal syndrome was associated with a higher probability of sustained major molecular response (P=0.003) and showed a trend for a longer time to major molecular response loss (P=0.098). Positivity (defined as ≥ 17 positive chambers) of digital polymerase chain reaction at screening and longer imatinib duration before imatinib discontinuation were associated with a higher probability of sustained major molecular response. Our data demonstrated that the occurrence of imatinib withdrawal syndrome after imatinib discontinuation and longer duration of imatinib were associated with a lower rate of molecular relapse. In addition, minimal residual leukemia measured by digital polymerase chain reaction had a trend for a higher molecular relapse. (Trial registered at ClinicalTrials.gov: NCT01564836).

Long-Term Follow-up of the French 1 Stop Imatinib Study (STIM1) in Chronic Myeloid Leukemia Patients

▪Background We previously demonstrated that Imatinib (IM) could be safely discontinued in patients with undetectable minimal residual disease (UMRD) of at least 2 years (Lancet oncology, 2010;11: 1029-1035). We report the update of the STIM1 study with a median follow-up (FU) of 65 months after IM discontinuation.Methods In this multicenter STIM study, imatinib (of >3 years duration) was prospectively discontinued in CML pts who were in deep molecular response (DMR) with UMRD sustained for at least 2 years. The UMRD was defined with sensitivity> to 4.5 log with ³ 50,000 ABL transcripts amplified as internal control. Importantly, the molecular relapse (MR) was defined as positivity of BCR-ABL transcript in quantitative RT-PCR confirmed by a second analysis point indicating the increase of one log in relation to the first analysis point, at two successive assessments, or loss of MMR at one point. Quantitative RT-PCR for BCR-ABL transcripts from peripheral blood was performed every month during the first year and every 2 months thereafter. In cases of molecular relapse, the treating physician was recommended to reintroduce TKI treatment. This study is registered with ClinicalTrials.gov, number NCT00478985Results From July 9, 2007, to Dec 17, 2009, 100 pts (48 male, 52 female) with CML (50 pts previously treated with interferon) and a median age at inclusion of 59 years (range 29-81) were included in the STIM trial. The median follow-up after treatment discontinuation is 65 months (range 9-84). Five pts died from CML-unrelated causes. Sixty-one pts relapsed of whom 17 have MMR loss at the time of relapse. MR occurred mostly within 6 months after IM discontinuation. Forty-nine (80% of relapsing patients) relapses occurred within month 1 to month 3, 9 (15%) within month 4 to month 7, 3 (5%) within month 18 to month 22. TKI was restarted in 57 out of 61 relapse pts and 55 achieved a second UMRD. With a median FU of 67 months, 39 pts remained free from MR. Among them, 16 were in sustained UMRD while 23 have intermittent positive BCR-ABL assessment without MR. None of the pts experienced a CML progression. The probabilities of relapse-free and treatment-free survivals at 6 months were respectively 43%, 59%; and at 24 months were respectively 38%, 41% after IM discontinuation (figure 1). For those patients who achieved the first 6 months without relapse (landmark analysis) the probability of relapse was 10% at 24 months.In order to identify factors associated with MR, several baseline characteristic of the study population cohort were analyzed, i.e; gender, age at diagnosis and at IM cessation, Sokal and Eutos risk scores, previous treatment with interferon, time from IM start to first UMRD, duration of UMRD before IM discontinuation and IM duration. Using univariate analysis only age and Sokal score were significant factors linked to MR (p=0.0364 and p=0.0210 respectively). Using multivariate analysis (including Age, gender, Previously IFN and duration of treatment) Sokal risk score was the only variable associated with a significant probability of MR (p: 0.0149 overall and odd ratio 7.422 IC95% :1.251-44.026 p=0.0273 for low versus high risk). With a median FU of 65 months, the cumulative duration of the "off treatment" period of the whole study population was 3113 months.Conclusion: With a median follow up > 5 years after stopping treatment, STIM study still demonstrates that IM can be safely discontinued in pts with a DMR of at least 2 years duration. MR occurs mostly during the first six months following IM discontinuation and no MR was recorded after 2 yrs. Treatment resumption in relapse patients was associated with the achievement of a second UMRD in almost all patients. [Display omitted] DisclosuresEtienne:BMS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ARIAD: Consultancy, Honoraria; PFIZER: Consultancy, Honoraria. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau. 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. Rousselot:BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:NOVARTIS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria, Speakers Bureau; PFIZER: Consultancy, Honoraria.

Dasatinib in Patients with Chronic Phase Chronic Myeloid Leukemia (CML-CP) with Persistent, Low-Grade Nonhematologic Toxicity to Imatinib: Results from Dasperse (CA180-400)

Background: Chronic, low-grade adverse events (AEs) are common in CML patients (pts) treated with the BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib (IM) and may decrease quality of life (Efficace, Blood. 2011;118:4554) and adherence to therapy (Marin, J Clin Oncol. 2010;28:2381). These AEs may result in dose modifications and contribute to suboptimal response. Alternative TKIs are available with the potential to reduce AEs, improve tolerability, and support long-term treatment goals. The second-generation TKI dasatinib (DAS) has demonstrated efficacy in pts previously treated with IM in the CA180-034 trial (Shah, Blood. 2014;123:2317). We present the analysis of CA180-400 (NCT01660906), an open-label, multicenter phase 4 study designed to determine if chronic, low-grade nonhematologic AEs in IM-treated pts improve after switching to DAS.Methods: Adult CML-CP pts who had not failed previous IM therapy (complete hematologic response by 3 mo, partial cytogenetic response [PCyR] by 6 mo, or complete cytogenetic response [CCyR] by 12 mo [Baccarani, Blood. 2013;122:872]) and had a chronic, grade 1/2 nonhematologic IM-related AE persisting for ≥2 mo or recurring ≥3 times in the prior 12 mo, despite best supportive care, were switched to DAS 100 mg once daily until disease progression, treatment failure, unacceptable AE, withdrawal of consent, or study discontinuation at 12 mo. The primary endpoint was the frequency of chronic, grade 1/2 nonhematologic IM-related AEs that decreased in grade or resolved within 3 mo following DAS initiation. Treatment-emergent DAS-related AEs and pt-reported symptom burden using MD Anderson Symptom Inventory (MDASI)-CML symptom severity and interference scores (0-10 scale; 10=worst) were also evaluated 3 mo following the switch to DAS.Results: Thirty-nine pts were enrolled in the trial. Median age was 57 y (range 23-81 y), with 31% ≥65 y. Median duration of prior IM was 47 mo and 49% had received <400 mg IM. Best response to IM at study entry was PCyR in 5% and CCyR in 69%; 69% also had major molecular response. A total of 123 chronic, grade 1/2 IM-related AEs were reported at baseline in the 39 pts; muscle spasms, facial edema, rash, myalgia, diarrhea, arthralgia, periorbital edema, and nausea each occurred in ≥10% of pts. Of the 123 AEs, 91 (74%) resolved completely, 2 (2%) improved in grade, 29 (24%) remained unchanged, and 1 (1%) worsened in grade within 3 mo of switching to DAS. All instances of edema either resolved or did not change, and similar results were reported for muscle spasms, rash, myalgia, diarrhea, arthralgia, and nausea (Table). Fatigue was the only IM-related AE that worsened on DAS. The majority of pts experienced improvement in ≥1 IM-related AEs, without the worsening of any other IM-related AE (overall, 34/39 [87%]; <65 y, 24/27 [89%]; ≥65 y, 10/12 [83%]). Treatment-emergent DAS-related nonhematologic AEs occurred in 29 (74%) pts within 3 mo and were mostly grade 1/2 (grade 3/4, 8/39 [21%]), including headache in 12, fatigue in 9, diarrhea in 7, and pleural effusion in 3. No pts had pulmonary arterial hypertension 3 mo following the switch to DAS. Two pts discontinued DAS due to toxicity (pleural effusion, extremity pain; sinus tachycardia, nausea, fatigue, headache). MDASI-CML symptom severity scores changed -0.6, -1.1, -1.4, -1.4 from baseline to 2 wk, 4 wk, 8 wk and 3 mo, respectively, and symptom interference scores changed -0.5, -1.0, -1.1, and -1.2 from baseline to 2 wk, 4 wk, 8 wk, and 3 mo, respectively, following DAS initiation, suggesting that symptom burden was reduced following the switch to DAS.Conclusions: In CA180-400, the majority of chronic, low-grade nonhematologic IM-related AEs resolved, and most others improved after switching to DAS. Pt-reported symptom burden was lower on DAS, and most physician-reported AEs were low-grade. Final, 1-year follow-up data, including efficacy, will be presented for all enrolled pts. [Display omitted] DisclosuresCleeland:Amgen Inc.: Consultancy. Saussele:Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding. Williams:Amgen: Consultancy; Novartis: Research Funding. Mohamed:BMS: Employment, Equity Ownership. Pinilla-Ibarz:Teva: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy.

High Prevalence of Peripheral Artery Occlusive Disease (PAOD) Among Patients with Chronic Myeloid Leukemia (CML) Receiving Tyrosine Kinase Inhibitors (TKIs): A Cross-Sectional Study

▪Background: Although TKIs become the standard of care in CML, the long-term complication has not been well recognized. There were reports of nilotinib associated metabolic derangements including diabetes and PAOD while these complications in other TKIs have not been well recognized.Objectives: To compare the prevalence of PAOD among CML patients and matched-control population.Methods: A cross-sectional case control study was conducted among CML patients receiving TKIs at Chiang Mai University Hospital between February to December 2014. The control group was matched by age, sex and diabetes. Screening PAOD using Fukuda VS-1500 to measure ankle-brachial index (ABI) and cardio-ankle vascular index (CAVI) for arterial stiffness were performed in both groups. The cutoff value of pathologic ABI and CAVI were less than 0.9 and higher than 8, respectively.Results: Seventy-eight CML patients and 156 matched-control population(1:2 ratio) were included. For CML patients, the median age was 55 years (21-86). Atherosclerotic risks including hypertension(20.5%), diabetes(12.8%), dyslipidemia(26.9%), metabolic syndrome(19.2%) and smoking(2.6%). Sixty-one patients(78.2%) were on imatinib, all as first-line, 13 patients(16.7%) on nilotinib (7.7%first-line, 92.3%second-line) while 4 patients(5.2%) were on dasatinib(all third-line). Median duration of imatinib, nilotinib and dasatinib treatment were 89.6, 46.7 and 22.1 months, respectively. The prevalence of pathologic ABI and CAVI were 9.0% and 26.7%, respectively. Patients receiving nilotinib had highest prevalence of abnormal ABI of 30.7% while patients receiving imatinib and dasatinib had abnormal ABI of 5% and 0%, respectively (p=0.004). Abnormal arterial stiffness by CAVI in nilotinib users were 15.4% compared to 27.8% and 50% in imatinib and dasatinib (p=0.815). Patients with CML had higher prevalence of pathologic ABI than in control group with an odds ratio(OR) of 2.09(95%CI 0.71-6.21, p=0.181). The only factor independently associated with pathologic ABI was level of HbA1C over 7 g/dl [OR2.41(95%CI 1.11-5.25; p=0.026)]. Age over 60 years [OR 3.95(95%CI 1.22-12.73, p=0.022)] and fasting plasma glucose over 126 mg/dl [OR 7.96(95%CI 1.21-52.26, p=0.031)] were independently associated with pathologic CAVI.Conclusions: The prevalence of PAOD by using ABI was higher among CML patients than in control population. CML patients receiving TKIs who have diabetes and older than 60 years old have a higher chance of developing PAOD and should be carefully monitored. DisclosuresNo relevant conflicts of interest to declare.

Multimodality therapy of rectal gastrointestinal stromal tumors in the era of imatinib-an Indian series.

Primary objective was to determine if sphincter preservation is possible with the use of neoadjuvant imatinib in cases of rectal gastrointestinal stromal tumor (GIST). Secondary objectives were to determine clinicopathological characteristics and intermediate term oncological outcomes of the cases of rectal GIST. This is a retrospective review of 13 cases of GIST of the rectum diagnosed between January 1, 2010 and June 30, 2015 at Tata Memorial Centre, Mumbai, India. Clinical parameters that were assessed were duration of the neoadjuvant imatinib therapy, type of surgery performed as well as perioperative morbidity. Pathological parameters that were assessed included the size of the tumor, completeness of resection, mitotic count and mutational analysis. Of the 13 patients included, 11 were nonmetastatic at the time of presentation. All the patients received neoadjuvant imatinib in view of locally advanced nature of the tumors. Median distance from anal verge was 2 cm. Median duration of imatinib was 9 months. Of the 9 patients who underwent surgery, three had sphincter preserving surgery (33%) whereas the rest had abdomino-perineal resection. Two patients had perineal wound infections. All the operated patients received adjuvant imatinib therapy for 3 years. Median follow up period was 34 months. One patient developed distant metastasis; otherwise rest had no local or distant recurrence. In cases of rectal GIST, sphincter preservation may not be possible in spite of neoadjuvant therapy with imatinib.

Sensitive allele specific oligonucleotide-polymerase chain reaction in detection of preexisting mutations in imatinib-resistant chronic myelogenous leukemia patients: A retrospective analysis

Introduction: Pre-existing BCR-ABL kinase domain mutation leads to Imatinib resistance. Methods: Retrospective analysis of 50 patients of Imatinib resistance was done in GCRI, from January 2014 till May 2014. Allelle Specific Oligonucleotide–Polymerase Chain Reaction (ASO-PCR) was performed on Genomic DNA, of peripheral blood mononuclear cells (PBMCs). Results: 47 (94%) were in Chronic phase, 2 (4%) in accelerated phase, 1 (2%) in blastic crisis. Median duration of Imatinib was 48 months. 43/50 had one or more than 1 mutation, T315I mutation in 5 (10%) patients, M351T in 32% (16/50) and F311L in 8. Conclusion: We report low cytogenetic response (25%) and durability of response to 600 mg of Imatinib, even in M351T mutation.

Results from the Korean Imatinib Discontinuation Study (KIDS): Updated Data with 15-Month Median Follow up

▪Background Approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD) at 6-7 years of first-line imatinib (IM) therapy. Although imatinib therapy is effective in chronic myeloid leukemia (CML) patients and a substantial portion of patients achieve UMRD with prolonged IM therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL1 in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent several reports to assess whether IM can be discontinued in CML patients have shown that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, the 12-month probability of sustained UMRD of 48 patients was 80.8% (78.4% in 37 patients with at least 12 months follow-up), a higher rate than that reported by the ‘STIM’ (Stop Imatinib) trial. To identify predictors for safer, successful IM discontinuation and to explore additional contributing factors for sustained molecular responses (MRs), this multicenter prospective Korean Imatinib Discontinuation Study (KIDS) is on-going.Methods Patients who were treated with IM for more than 3 years and whose BCR-ABL1 was undetectable in RQ-PCR for at least 2 years were enrolled in this study. After discontinuation, molecular response was monitored using RQ-PCR assay every month up to 6 month follow-up, every 2 months up to 12 month follow-up, and every 3 months thereafter. In case of relapse, defined as loss of MMR on 2 consecutive assessments, IM therapy was re-introduced and molecular response after resumption was observed every month using RQ-PCR. Our primary objectives were to evaluate the probability of persistent UMRD at 12 month follow-up after discontinuation, and to measure the duration of persistent UMRD after discontinuation. The secondary objective was to evaluate the probability of major molecular response (MMR) loss and the time taken to lose MMR after discontinuation.Results Of the 148 patients who were screened for KIDS, 30 patients have failed because of positive result of RQ-PCR tested in the central laboratory (N= 21, 70%), failure to meet inclusion criteria (N=7, 23%) and informed consents withdrawal (N=2, 7%).As of data cut-off date of 2 July 2014, a total of 115 patients (66 females, 49 males) who were diagnosed between 20 Mar 1996 and 12 Jul 2012 were enrolled on KIDS, with a median age of 44 years (range, 19 – 77), the percentages of patients with low, intermediate and high Sokal risk scores were 35%, 25% and 17%, respectively with unknown Sokal risk scores in 23%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 84 months (range, 32 – 149) and 44 months (range, 22 – 131), respectively.With a median follow-up of 15 months (range, 0.2 – 45.4), 28 patients loss MMR and the probability of sustained MMR was 73.5 ± 4.3%. The 12-month probability of sustained MMR was 67.0 ± 5.2%.Among 21 patients who lost UMRD without confirmed MMR loss, 10 spontaneously re-achieved UMRD, 2 fluctuated BCR-ABL1 transcript under MMR and 9 continuously increase BCR-ABL1 transcript. All of 28 patients who confirmed MMR loss were re-treated with IM for a median of 9.9 months (range, 0.7 – 34.2 months), 22 patients re-achieved MMR at a median of 4.1 months (range, 0.5 - 6.5 months) after resuming IM therapy and 14 of these patients re-achieved UMRD at a median of 6.7 months (range, 3.3 - 13.3 months). One patient, who lost MMR at 7.6 months after KIDS enrollment, resuming IM for 26.7 months and sustained UMRD for 23.9 months, currently discontinues IM therapy (KIDS2) with the follow up of 6.5 months. Univariate analysis showed that IM duration and UMRD duration before treatment discontinuation had a higher 12-month probability of sustained MMR.Conclusions Based on results, IM discontinuation with resuming after MMR loss can be applied safely. In particular, the rate of screening failure due to positive result of RQ-PCR tested in the central laboratory implied that a strict PCR sensitivity criterion is important for safer, successful IM discontinuation. Overall, both UMRD and IM duration on treatment were the most important predictors for successful IM-off. Further studies on underlying mechanisms about immunological control, minimal residual leukemia and stem cell biology during TKI-off study should be conducted. DisclosuresNo relevant conflicts of interest to declare.

A Novel Approach to a Retrospective Longitudinal Analysis of Dose Change or Discontinuation of Imatinib Therapy in Chronic Phase–Chronic Myeloid Leukemia

▪Imatinib (IM) is a cornerstone in the treatment of chronic myeloid leukemia (CML). Dose change or discontinuation of IM in patients who experience sustained molecular response is a subject of debate.We retrospectively studied 142 CML patients in chronic phase (Table 1) treated with IM and followed-up during 2000-2013 at our institution. Dose changes, discontinuation of therapy, cytogenetic and molecular analyses were regularly recorded during follow-up. Patients’ history was subdivided into 483 treatment time-periods at constant dosage. Response was evaluated at the end of each treatment period. We assessed whether the probability of observing a complete cytogenetic response (CCyR) or a molecular response (MR: complete, CMR or major, MMR) or a progression were influenced by treatment dose and/or duration.We applied generalized estimating equation (GEE) logistic models for the analysis of longitudinal panel data. These models are designed to account for individual patient variation due to repeated measurements during each patient’s follow-up.Out of 483 time periods at constant IM dose, 236 were followed by dose modification, 116 by IM discontinuation, 29 by a change to other treatments due to tolerability issues or non-response; 102 were still ongoing without dose changes.Treatment response: 74% of time periods resulted in a CCyR and 2.3% showed no response; 31.9% showed a CMR, 29.6% showed a MMR (MR3, MR4, MR4.5), 35.6% a suboptimal response, 2.9% no MR. CMR+MMR was observed in 61.5% time periods.Periods at standard dose showed a higher response rate, both when considering CCyR (response rate after low, standard, high dose: 69.3%, 79.6%, 68%, respectively, P=0.023) and when considering MR (CMR after low, standard, high dose: 27%, 40.5%, 15.4%, respectively, P<0.001; CMR + MMR after low, standard, high dose: 53.4%, 69.8%, 52.3%, respectively, P=0.001).After adjusting for length of treatment period in a multivariate GEE model, dose lost significance and treatment duration was the only significant predictor of CCyR (P<0.001).In a GEE analysis of MR accounting for treatment duration, reduction in CMR rate after periods at high dose compared with periods at standard dose remained significant (P=0.025). Treatment dose lost significance when considering CMR+MMR.In 32 patients who discontinued IM therapy for >1 mos and then re-started IM, the CR rate after a period preceded by a treatment suspension was significantly higher than in other periods (CCyR: 85.7% vs. 73%, P=0.058; CMR 55.1% vs. 29.3%, P=0.001). In a GEE model with dose category, duration of treatment and previous suspension as covariates, both duration and previous suspension maintained a positive significant association to CCyR (P<0.001, P=0.034, respectively), to CMR (both P<0.001) and to CMR+MMR (P<0.001, P=0.006, respectively).Cytogenetic progression rate at the end of a period of IM treatment was 7.1% while molecular progression rate was 12.8%.Treatment dose was not associated to progression: cytogenetic progression after low, standard, high dose: 6.1%, 6.7%, 10.5%, respectively, P=0.428; molecular progression after low, standard, high dose: 14.8%, 11.3%, 13%, respectively, P=0.584. In a multivariate GEE analysis, neither dose nor duration of treatment predicted progression. After adding type of previous treatment (IM, other drug, no treatment) as a covariate, treatment periods preceded by at least 1 month of discontinuation had a significantly lower molecular progression rate (P=0.011).The possibility of varying dosage is often considered in “real-life” patient clinical management. In our study, 62% of time periods were followed by a dose change, but this did not affect response and progression rate after accounting for length of treatment period. The prompt response to resumed IM therapy suggests that patients may be candidates for intermittent therapy.Future studies could use the same statistical model to pick up individual patient variation in longitudinal data collected over time, including trials at reduced IM dose or of “on-off” therapy or on new TKI.Table 1Patients’ characteristicVariableDescriptionN. of patients142Sex M/F58%/42%Age at diagnosis (years), median (range)52 (18-78)N. of IM treatment periods483IM dosage, N (%)Low dose (100-300 mg/day)163 (34%)Standard dose (400 mg/day)242 (50%)High dose (450-800 mg/day)78 (16%)Duration of IM at constant dosage (days), median (range)258 (7-4526) DisclosuresNo relevant conflicts of interest to declare.

Hyperhomocysteinemia and High Doses of Nilotinib Favour Cardio-Vascular Events in Chronic Phase Chronic Myelogenous Leukemia (CML) Patients

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. [Display omitted] 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. DisclosuresMichallet: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.

Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib

AbstractMyeloid neoplasms and eosinophilia with rearrangements of PDGFRB are uncommon Philadelphia-negative myeloproliferative neoplasms. Patients are typically male, with morphologic features of a Philadelphia-negative chronic myeloproliferative syndrome or chronic myelomonocytic leukemia with eosinophilia. Reciprocal translocations involving PDGFRB result in fusion genes with constitutively activated receptor tyrosine kinase sensitive to inhibition with imatinib. We present an updated and expanded analysis of a cohort of 26 such patients treated with imatinib. After a median follow-up of 10.2 years (range, 1.8-17 years), the 10-year overall survival rate was 90% (95% confidence interval, 64%-97%); after median imatinib duration of 6.6 years (range, 0.1-12 years), the 6-year progression-free survival rate was 88% (95% confidence interval, 65%-96%). Of the patients, 96% responded; no patients who achieved a complete cytogenetic (n = 13) or molecular (n = 8) remission lost their response or progressed to blast crisis. Imatinib is well-tolerated and achieves excellent long-term responses in patients with PDGFRB rearrangements.

Prediction Of Second Generation Tyrosine Kinase Inhibitors Response After Imatinib Failure: The Value Of The Hammersmith Prediction Score

Second generation tyrosine kinase inhibitors (TKI2) have been introduced as 2nd line therapy for chronic myeloid leukemia (CML) failing imatinib (IM) in 2005. In order to optimize the therapeutic strategy and the decisions to be made for chronic phase (CP) CML patients (pts) in this situation, a prognostic score has been established in the Hammersmith hospital (Milojkovic et al. Haematologica 2009) to segregate patients and predict their response to TKI2. However, this score relies on limited data from 2 centers and might not be representative of CP CML pts failing IM. The primary objective of this national study was to retrospectively and prospectively analyse the predictive value of this score in CP CML resistant or intolerant to IM pts from numbers of academic institutions (university and non-university hospitals). All molecular analyses performed locally were standardised according to the IS system since 2005. One hundred and seventy four CP CML cases have been enrolled in 22 centers and their data collected after informed consent, between 2009 and 2012. There were 89 males (51%) and 85 females with a median age at enrolment of 61 (25-86). Sokal score was low for 39%, intermediate for 31% and high for 30 % (5 pts unknown). A minority of patients had IFN-a prior to IM (27%), and none were allotransplanted previously. The median time between diagnosis and IM initiation was 1.4 (0-321) months, IM dose was modified in 138 pts (80%), 98% of pts experienced CHR on IM, 52% CCyR and 29% MMR. Twenty pts (12%) were neutropenic on IM and overall IM duration was 31.2 (0.5-99) months. At TKI2 initiation (63% dasatinib, 37% nilotinib), 128 pts were in CHR (74%), 53 in CCyR (30.5%), 24 in PCyR(14%), 11 (6%) in minor CyR, 13 (7.5%) in minimal and 41 (24%) with no CyR (32 pts: no cytogenetic data available), 137 (79%) pts were in less than major MR, 45.5% harboured a BCR-ABL mutation. One hundred and ten (63%) pts were IM-resistant (molecular 40%, cytogenetic 24.5%, hematologic 8.5%) and 97 (56%) IM-intolerant (considering that some pts can be resistant and intolerant altogether), because of skin, liver, hematologic and gastro-intestinal toxicities mainly. Hammersmith scores (HS) were low (L<1.5) for 89 (65%), intermediate (I) for 28 (20%) and high (H≥2.5) for 20 (15%) pts, incalculable for 37 pts, excluded from the analysis. No statistical difference was observed between the two TKI2 in all variables analysed. Twenty-three percent obtained CHR on TKI2 (3% did not and 74% were already in CHR at TKI2 initiation), 51.5% of evaluable pts were in CCyR at M3, 69% at M6, and 74% at M12; 23% were in MMR at M3, 28% at M6, 36.5% at M12, 8% in MR4.5 at M3, 18% at M6, 19% at M12. At 12 months, 73 pts remained on the first TKI2 with 71 (97%) in CHR, 11 (15%) in CCyR and 31 (42.5%) in MMR, with 47.5% switching to another TKI2 because of resistance (22%) and/or intolerance (19%) to a first TKI2. After a median follow-up of 53 (6-94) months since TKI2 initiation, 2% progressed to accelerated phase, 6% to blast crisis, and 17 (10.5%) died mostly because of CML. A Cox model multivariate analysis demonstrated that a L HS was significantly associated with a better OS (p=0.0062), but not on FFS (p=0.16). Figure 1 shows the failure free survival* to TKI2 according to the HS. Multivariate analyses demonstrated the favourable impact having obtained a CCyR on IM (HR: 2.5, 95%CI: 1.4-4.6, p=0.0021); the negative impact of age 55-65 years at TKI2 initiation (HR: 0.26, 95%CI: 0.1-0.6, p=0.0032) on CCyR rates; and the positive impact of having obtained previous molecular response (≥MMR) on IM (HR: 2.8, 95%CI: 1.79-4.25, p<0.0001) on MMR rates on TKI2. ROC curves and logistic regression analyses demonstrated the predictive value of the HS on CCyR rates (AUC 0.81; HR: 21.4, 95%CI: 4.3-105, p=0.0002) and on ≥MMR rates (AUC: 0.67; HR: 4.5, 95%CI: 2.-10.3, p=0.0003) on TKI2. In conclusion, this retrospective and prospective multicentric analysis performed on large number of pts demonstrated a significant relationship between the HS value and the level of cytogenetic and molecular responses on TKI2 after IM failure and overall survival in the multivariate analysis. [Display omitted] *Failure is defined as: No hematologic or cytogenetic response, CHR, CCyR, PCyR MMR or MR4.5 loss, death, progression to AP/BC, definitive TKI2 cessation for resistance or intolerance, allogeneic stem cell transplantation. Disclosures:Nicolini:Novartis, Ariad, Teva, BMS and Pfizer: Honoraria from Novartis, Ariad, Teva, BMS and Pfizer. Grants from Novartis. Other. Rousselot:BMS, Ariad, Pfizer: Honoraria from BMS, Ariad, Pfizer. Grants from BMS Other. Giraudier:Novartis, BMS: Honoraria. Etienne:Novartis, BMS, Pfizer and Ariad: Honoraria. Roy:Novartis, BMS: Honoraria. Cony-Makhoul:BMS: Honoraria. Marie:BMS: Employment. Mohamed:BMS: Employment. Rea:Novartis, BMS, Teva and Pfizer: Honoraria.

Prescribing decision drivers in patients with recurrent gastrointestinal stromal tumor (GIST) previously treated with adjuvant imatinib: A retrospective chart extract-based approach.

e21515 Background: Adjuvant imatinib (IM) is the standard of care for primary resectable GIST. However, little is known about prescribing habits following disease recurrence. This study identifies main prescribing decision drivers in recurrent GIST pts following completion of adjuvant IM treatment. Methods: Using an online data collection system, clinical information was retrieved on 410 pts treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, who discontinued IM treatment, had a recurrence (while off IM), and subsequently restarted IM or initiated sunitinib. Pt-level data were collected at primary diagnosis and at first recurrence. Prescribing decision drivers were identified using logistic regression models. Physicians were also surveyed to identify factors that influence their prescribing decisions. Results: Following initial disease recurrence, 77% of pts restarted IM and 23% initiated sunitinib. IM duration at primary diagnosis was the main prescribing decision driver; pts treated with IM for a shorter period of time (≤18 months) were 7.0 times more likely to restart IM than pts with longer IM duration (p&lt;.01). Pts who took longer (≥12 months) to develop recurrence after IM discontinuation (Odds ratio [OR]=3.4; p=&lt;.01 ), had a low mitotic rate at recurrence (OR=2.8; p=&lt;.01), or had a recurrence inside the gastrointestinal system (OR=2.7; p=&lt;.01) were also more likely to be prescribed IM following recurrence. These findings were consistent with the top survey responses on factors influential to prescribing decisions after recurrence: time to develop recurrence (55%), pt risk profile (53%), and IM duration prior to recurrence (51%). Conclusions: Based on information of pts who restarted IM or initiated sunitinib, IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location and mitotic rate at recurrence seem to be the main prescribing decision drivers. These findings were consistent with physicians’ main factors reported to influence their prescribing decisions following recurrence.

Results from a phase III trial (GRID) evaluating regorafenib (REG) in metastatic gastrointestinal stromal tumour (GIST): Subgroup analysis of outcomes based on pretreatment characteristics.

10551 Background: REG, an oral receptor kinase inhibitor with activity against KIT, PDGFR, VEGFR, FGFRs, and other oncologic targets, demonstrated significant improvement in progression-free survival (PFS) over placebo (PL) in a phase III study (GRID) of patients (pts) with advanced GIST following failure of at least imatinib (IM) and sunitinib (SU). To understand the impact of pts’ baseline characteristics on outcome, we performed an exploratory analysis of REG effects across pt subgroups based on sex, age, and mitotic index of primary GIST tissue, as well as duration and number of lines of previous therapies. Methods: Adult pts with metastatic GIST (n=199) progressing after at least IM and SU were randomized 2:1 to receive oral REG 160 mg or PL once daily for the first 3 weeks of each 4-week cycle. Subgroup analysis of centrally assessed PFS was performed, based on sex, age (&lt;65, ≥65 years), mitotic index of primary GIST (&lt;5, ≥5 to &lt;10, ≥10 mits/50 hpf), duration of IM and SU treatment (&lt;6, ≥6 to &lt;18, ≥18 months), and number of prior anticancer treatment lines (2 or ≥3). Mitotic index data on primaries were available for 119 patients. Results: REG demonstrated improvement in PFS vs PL in all subgroups, as summarized in the Table. Conclusions: REG had substantial efficacy in all patient subgroups included in this analysis. Clinical trial information: NCT01271712. [Table: see text]

Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib

Although recent studies have suggested that cessation of imatinib (IM) in chronic myeloid leukemia patients can be associated with sustained response, further validation is needed to explore predictive factors. In a prospective, multicenter study, chronic phase patients were eligible for cessation of IM therapy after more than 3 years if they had no detectable BCR-ABL1 transcript for at least 2 years. A total of 48 patients with a median age of 47 years (19-74 years) were enrolled. Twenty patients received IM for post-transplant relapse. After a median follow-up of 15.8 months (1.4-28.2 months) after IM discontinuation, nine of the non-transplant group lost undetectable molecular residual disease (UMRD) and major molecular response (MMR), whereas none of the 20 patients in the transplant group experienced UMRD loss. Probabilities for sustained MMR and UMRD were 64.4% and 66.3% in the non-transplant group, respectively. Of nine patients re-treated with IM, eight patients re-achieved MMR at a median of 1.7 months (0.9-2.8 months). Seven of these patients re-achieved UMRD at a median of 5.6 months (2.8-12.1 months). Previous transplantation, IM duration, and UMRD duration were significantly associated with sustained molecular responses. Our data strongly suggest that immunological control contributes to sustained suppression of residual leukemia cell expansion and that IM can be safely discontinued in patients with post-transplant relapse.

Efficacy observation on imatinib adjuvant therapy with longer duration in patients with gastrointestinal stromal at intermediate or high risk of recurrence

To evaluate the recurrence-free survival (RFS) and safety of imatinib adjuvant therapy with longer treatment duration in patients undergoing complete resection of localized primary gastrointestinal stromal tumor (GIST). Clinical and follow-up data of 101 GIST patients between March 2004 and May 2009 with intermediate or high recurrence risk receiving imatinib adjuvant treatment and more than 3 years follow-up time in Peking University Cancer Hospital were retrospectively analyzed. Imatinib adjuvant treatment: 3 patients discontinued less than 1 year imatinib treatment because of adverse events; 24, 21 and 18 patients discontinued imatinib after 1 year, 2 years, and 3 years treatment; 8 patients received 3 years adjuvant treatment and were ongoing; 27 patients received more than 4 years imatinib adjuvant treatment. The median follow-up time was 60 months (95%CI:57.9-62.1). Nineteen patients had GIST recurrence, of whom recurrence happened during imatinib adjuvant therapy in 5 patients and after imatinib treatment in 14 patients. The median period from imatinib stopping to recurrence was 12.0 months (95%CI:9.6-14.4). Patients with recurrent GIST achieved tumor control after imatinib resumption. RFS of patients (n=53) with ≥3 years imatinib treatment duration was higher than that of patients (n=48) with <3 years imatinib duration (93.9% vs. 68.0%, P<0.01). In addition, prolonged adjuvant imatinib duration did not significantly increase the adverse events related to treatment (P>0.05). Prolonged adjuvant imatinib duration may further improve RFS rate further in patients with intermediate or high risk of recurrence after complete tumor resection without increased adverse events.

Randomized phase II study of 6 versus 12 months of adjuvant imatinib for patients with intermediate- or high-risk GIST.

9 Background: The Z9001 study revealed adjuvant imatinib for 1 year significantly improved RFS in GIST patients (pts). The SSGXVIII study compared 3 years with 1 year of adjuvant imatinib for high risk GIST pts, but there was no study to evaluate shorter period of imatinib administration than 1 year. We conducted a randomized phase II study to compare 6 months (6-mo) with 12 months (12-mo) adjuvant imatinib for intermediate or high risk GIST pts. Methods: Inclusion criteria included ECOG-PS of 0 or 1, age between 20 and 79 years, and primary KIT-positive GIST with intermediate or high risk according to the Fletcher criteria. Pts were randomized assigned to the 6-mo or 12-mo treatment of imatinib 400 mg/day after complete resection. The primary endpoint was recurrence-free survival (RFS). The study was designed as a randomized screening trial to evaluate non-inferiority with margin of hazard ratio 1.67, 1-sided alpha 0.2 and power 0.8. Results: Ninety-two pts were randomly allocated the 6-mo group (n=45) or the 12-mo group (n=47) between Dec 2007 and Aug 2011, which was well balanced for baseline characteristics. One patient was ineligible due to non-GIST (desmoid) tumor at a central review. The proportions of pts completed their assigned adjuvant treatment were 80% in the 6-mo and 70% in the 12-mo group. The first interim analysis was conducted at Sep 2012 with the median follow-up time of 33 months. The 1- and 2-year RFS were 82% and 65% in the 6-mo group and 96% and 86% in the 12-mo group, respectively. Hazard ratio of recurrence was 1.81 (95%CI: 0.84-3.91), and the 2-sided log-rank p value was 0.12. Adjuvant imatinib was well tolerated, with one patient of Gr. 4 rash and no treatment-related death. Because of the lower efficacy of the 6-mo group than expected, the Data and Safety Monitoring Committee recommended the early release of first interim analysis results. Conclusions: Adjuvant Imatinib for 6-mo was inferior in efficacy to that for 12-mo in terms of RFS. Shortening of the adjuvant imatinib duration is not recommended for intermediate or high risk GIST pts. Clinical trial information: UMIN000000950.