Imatinib Cessation Research Articles

Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia.

The registered dose for imatinib is 400 mg/d, despite high inter-patient variability in imatinib plasmatic exposure. Therapeutic drug monitoring (TDM) is routinely used to maximize a drug’s efficacy or tolerance. We decided to conduct a prospective randomized trial (OPTIM-imatinib trial) to assess the value of TDM in patients with chronic phase chronic myelogenous treated with imatinib as first-line therapy (NCT02896842). Eligible patients started imatinib at 400 mg daily, followed by imatinib [C]min assessment. Patients considered underdosed ([C]min < 1000 ng/mL) were randomized in a dose-increase strategy aiming to reach the threshold of 1000 ng/mL (TDM arm) versus standard imatinib management (control arm). Patients with [C]min levels ≥ 1000 ng/mL were treated following current European Leukemia Net recommendations (observational arm). The primary endpoint was the rate of major molecular response (MMR, BCR::ABL1IS ≤ 0.1%) at 12 months. Out of 133 evaluable patients on imatinib 400 mg daily, 86 patients had a [C]min < 1000 ng/mL and were randomized. The TDM strategy resulted in a significant increase in [C]min values with a mean imatinib daily dose of 603 mg daily. Patients included in the TDM arm had a 12-month MMR rate of 67% (95% CI, 51–81) compared to 39% (95% CI, 24–55) for the control arm (p = 0.017). This early advantage persisted over the 3-year study period, in which we considered imatinib cessation as a censoring event. Imatinib TDM was feasible and significantly improved the 12-month MMR rate. This early advantage may be beneficial for patients without easy access to second-line TKIs.

Low Natural Killer (NK) Cell Counts and Functionality Are Associated With Molecular Relapse After Imatinib Discontinuation In Patients (pts) With Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) With Undetectable BCR-ABL Transcripts For At Least 2 Years: Preliminary Results From Immunostim, On Behalf Of STIM Investigators

BackgroundIn pts with CP-CML, the notion that tyrosine kinase inhibitors (TKI) may never be stopped is currently challenged in the setting of clinical trials. In the pioneering French STIM trial, pts on imatinib for at least 3 years who had achieved and maintained undetectable BCR-ABL transcripts for at least 2 years had a 24-month molecular relapse-free survival of 39% with no relapses beyond 24 months. A low Sokal risk group and a long-lasting imatinib treatment were significantly associated with an increased freedom from molecular relapse but the role of other factors such as cellular immunity cannot be excluded. The aim of IMMUNOSTIM performed on a subset of 51 pts enrolled in the STIM trial was to analyze the potential implication of NK-cell and T-cell immunity in molecular relapse-free survival after imatinib discontinuation. MethodsPeripheral blood was drawn prior to and after imatinib cessation. All analyses were performed in a centralized fashion. Blood cell counts and differentials were determined using an automated blood cell count analyzer. Flow cytometry was performed on fresh cells to quantify CD56dim and CD56bright NK cells, CD3+ T cells, naïve and memory CD4+ and CD8+ T cells and CD4+ regulatory (CD25+CD127neg/low) T cells (TREGs). Expression of activating and inhibitory NK cell receptors was also analyzed. Functional analyses were performed using frozen mononuclear cells. The focus was put on NK cell function by means of a CD107a degranulation assay against the K562 cell line and an IFN-g secretion assay upon IL-12 and IL-18 stimulation. ResultsStudied pts' characteristics were comparable to that of the entire STIM study population. Median age was 63 years, 64.7% of pts were females and 52.9% has received prior IFN. Sokal risk group was low in 54.9%, intermediate in 35.3%, high in 7.8% and unknown in 2%. Median imatinib treatment duration was 57 months (36-94). Median follow-up after imatinib discontinuation was 42 months (24-54). A molecular relapse occurred in 28 pts after a median time off therapy of 2 months (1-20). Median BCR-ABL/ABL transcript ratio at relapse confirmation was 0.015% IS (0.006-1.546). Molecular relapse-free survival at 24 months was 47.1% (95% CI: 31.4-58.7). A significantly higher proportion of low low Sokal risk group and a trend toward longer imatinib treatment duration were found in pts who did not relapse compared to those who relapsed.At baseline, median leucocyte and lymphocyte counts were 4820/mm3 (2550-7860) and 1310/mm3 (720-2610), respectively and were comparable in pts who relapsed and those who did not. Median CD3+, CD4+, CD4+ TREGs, CD8+ T cells and CD4/CD8 ratio were 879/mm3 (315-1949), 534/mm3 (228-1248), 37/mm3 (4-94), 279/mm3 (72-998) and 2 (0.5-14.2), respectively, with no significant difference between pts who relapsed and those who did not. Analysis of CD4+ and CD8+ naïve, effector and central memory T cells did not reveal any differences between the 2 groups.In contrast, NK cell counts at imatinib cessation were significantly lower in pts who relapsed than in those who did not relapse (145/mm3 (67-450) versus 233/mm3 (70-727), p=0.0146). This decrease specifically affected the cytotoxic CD56dim population. NK cells numbers did not significantly increase in either group after imatinib discontinuation.NK receptor expression analysis did not show any significant defect in the expression of the activating NKG2D receptor and the CD94, NKG2A and KIR inhibitory receptors. However, the cytotoxic activity of CD56dim NK cells toward K562 and the IFN-g secretion potential of CD56bright NK cells upon IL-12 and IL-18 stimulation were significantly decreased when compared to those of healthy donors. Analyses are ongoing to further dissect NK cell function in pts who relapsed and those who did not. Updated results will be presented. ConclusionsOur stud shows a specific association between peripheral blood NK cells and clinical outcome after imatinib discontinuation in pts with long-lasting molecularly undetectable residual disease. These results suggest that NK cell-based immune surveillance may contribute to CML control after TKI cessation. Whether NK cells may be used as biomarkers among other factors to predict disease relapse after TKI cessation needs to be investigated. The understanding of NK cell defects may help in building strategies to restore an optimal NK cell-mediated anti-leukemic activity. Disclosures:Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Nicolini:Novartis, Ariad and Teva: Consultancy; Novartis & Bristol Myers Squibb: Research Funding; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis, BMS, Teva: Speakers Bureau; Novartis, Ariad, Teva, Pfizer: Membership on an entity's Board of Directors or advisory committees. Rousselot:BMS, Ariad, Pfizer: Honoraria from BMS, Ariad, Pfizer. Grants from BMS Other.

BCR-ABL1 Transcript Doubling Time after Imatinib Discontinuation for Treatment-Free Remission in Chronic Myeloid Leukemia in Chronic Phase: Predictor for Treatment-Free Remission Failure

BCR-ABL1 Transcript Doubling Time after Imatinib Discontinuation for Treatment-Free Remission in Chronic Myeloid Leukemia in Chronic Phase: Predictor for Treatment-Free Remission Failure

Ddeeper Than Deep: Can ddPCR Predict Successful Imatinib Cessation?

BCR-ABL1 transcripts at imatinib cessation were quantified by droplet digital PCR (ddPCR) for 175 patients on the STIM2 trial. Patients with BCR-ABL1 transcripts below a defined cutoff had a 12-month molecular recurrence rate of 46% versus 68% for those above the cutoff. Implications of using ddPCR in forecasting successful imatinib cessation are discussed.See related article by Nicolini et al., p. 6606.

Genotypes of the Gene Encoding the Membrane Transporter SLC22A4 Are Associated with Molecular Relapse-Free Survival after Discontinuation of Imatinib Therapy in Patients with Chronic Myeloid Leukemia

Introduction: The single nucleotide polymorphism (SNP) rs460089 (G/C) located in the promotor of SLC22A4 (transporter hOCTN1) was identified as a prognostic factor for the outcome of chronic myeloid leukaemia patients treated with imatinib first line (Jaruskova et al. JECCR 2017). Patients with GC genotype had significantly higher probability of achievement of sustained major molecular response (MMR, BCR-ABL≤0.1% IS) as compared with patients with GG. We investigated differences in the outcome after imatinib cessation in EURO-SKI patients according to the genotypes of the SNP rs460089. Methods: DNA analysis was performed by TaqMan SNP genotyping assay using StepOnePlus RQ-PCR System (Thermofisher Scientific). In addition to the inclusion criteria defined for prognostic analysis in Saussele et al. (Lancet Oncology 2018), all patients with interferon pre-treatment were excluded. Data on sex, duration of IM treatment, of deep molecular response and age at time of imatinib discontinuation as well as molecular status at 6 months thereafter were available for 178 patients. Logistic regression was used to investigate factors affecting MMR maintenance at 6 months. Level of significance was 0.05. Results: Of 178 patients, 106 (60%) maintained MMR 6 months after imatinib stop. GC genotype was identified in 64 patients, GG in 96 and CC in 18. Most beneficial for MMR maintenance was genotype GC (72%, 95% confidence interval (CI): 60-82%), followed by CC (61%, CI: 38-80%) and GG (51%, CI: 41-61%). Overall, the SNP rs460089 was associated with MMR maintenance (p=0.0335) with a significantly higher odds ratio (OR) for maintenance for GC genotype vs. GG (2.451, CI: 1.247-4.819, p=0.0093) but not for CC vs. GG (1.507, CI: 0.539-4.216, p=0.4343). Only duration of TKI treatment was significant (OR: 1.157, CI: 1.014-1.319, p=0.0303) when added to genotypes in multiple regression. The OR of GC vs. GG was slightly modified to 2.311 (1.164-4.588, p=0.0166). Conclusions: Based on observed data we suppose that the GC genotype of the SNP rs460089 is associated with sufficient intracellular concentration of imatinib allowing more efficient targeting of CML cells during the treatment. This resulted in a higher proportion of patients who sustained MMR after imatinib stop as compared with patients with GG. Longer duration of imatinib treatment increased the probability of MMR maintenance after imatinib cessation also in patients with GG. The frequency of CC was low and outcome in between GC and GG. The SNP rs460089 may provide an independent prognostic factor for molecular response maintenance after imatinib cessation. Supported by MZCR 00023736. Disclosures Machova: Novartis: Consultancy; BMS: Consultancy, Research Funding; Incyte: Consultancy. Fabarius:Novartis: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Merck: Consultancy; Ariad: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy. Burchert:Novartis: Research Funding. Mustjoki:BMS: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Žáčková:Bristol Myers Squibb: Consultancy; Angelini: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Panayiotidis:Bayer: Other: Support of clinical trial. Richter:Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Hjorth-Hansen:BMS: Research Funding; Pfizer: Consultancy, Research Funding; Austrian Orphan Pharma: Consultancy, Research Funding. Saussele:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria, Research Funding.

Killer immunoglobulin-like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment-free remission.

Background Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin‐like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells. Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2. Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B‐positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32‐0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment‐free remission rates. Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte‐mediated control of leukemic residual disease control in patient with CML relapse.

Discontinuation of imatinib in children with chronic myeloid leukaemia in sustained deep molecular remission: results of the STOP IMAPED study.

This international study aimed to assess the effect of imatinib discontinuation in paediatric patients with chronic myeloid leukaemia (CML) after deep molecular remission (DMR) had been achieved and maintained for at least 2years. The primary endpoint of this analysis was the molecular relapse-free survival, estimated by the non-parametric Kaplan-Meier method. Major endpoint was the estimated rate of patients without molecular relapse at 6months. Fourteen patients were enrolled; 4 patients maintained DMR with a follow-up of 24 (two patients), 34 and 66months, respectively, whereas 10 patients relapsed. All molecular relapses occurred within 6months (median 3months, range 1-6) after imatinib discontinuation. The overall probability of maintaining DMR at 6months was 28·6%. No parameters associated with molecular relapse could be identified. Keeping in mind the rarity of paediatric CML, which contributed to the small size of the cohort, our findings illustrate that imatinib cessation after sustained DMR is successful in only limited numbers of patients, whereas much higher rates are reported in adult patients. Further research is needed to extend the cohort of paediatric CML patients who might achieve treatment-free remission with an ideal prerequisite of predicting the occurrence of molecular relapse l after imatinib cessation.

The Evaluation of Residual Disease By Digital PCR, and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after for Stopping Imatinib First-Line in Chronic Phase CML Patients: Results of the STIM2 Study.

BackgroundTKI discontinuation is now a critical goal of CML management and several studies have demonstrated the feasibility of stopping safely imatinib (IM). A sustained deep molecular response (DMR) on long-term TKI therapy seems critical prior to attempting treatment-free remission (TFR). Results from different studies have been reported recently, but they failed to identify robust and reproducible predictive factors allowing a better selection of candidate patients for successful TFR.AimsWe prospectively asked whether the use of IM first-line in de novo CP-CML patients and a systematic screen of patients with digital droplet quantitative PCR (ddPCR) for BCR-ABL1 would impact on the TFR rates.MethodsIn a national prospective phase II trial (Eudract # NCT01343173), we enrolled newly diagnosed CP-CML patients, in sustained MR4.5 (≥2 yrs on at least 5 consecutive points) according to the ELN criteria, checked centrally. Further molecular follow-up was performed in local laboratories, all ELN standardized and aligned on the international scale (IS). Molecular recurrence was defined as the positivity of BCR-ABL1/ABL1 transcripts with at least 1-log increase between 2 consecutive assessments or as loss of MMR on a single assessment. Duplex ddPCR was performed on screening samples after RT, using EAC primers and probes. Pre-mixes were transferred in aDG8 cartridge, and generation of droplets was made on the QX200 droplet generator. Each emulsion was transferred into a 96 wells ddPCR plate and amplified on the Biorad-C1000 Touch Thermocycler. Each patient was analyzed in duplicate. ddPCR was considered positive when the BCR-ABL1/ABL1 % was ≥3 SD. BCR-ABL1/ABL1 ratios were aligned on the IS, a conversion factor was calculated for the RT-ddPCR as previously described (S. Branford et al., Blood 2008). Impact of variables on the risk of relapse were assessed through univariate and multivariate analyses using SAS program.ResultsThe median follow-up after IM cessation was 23.5 (1-64) Mo. One patient died from unrelated cause, and 107 experienced a loss of MMR. The molecular recurrence-free survival (RFS) was 52% (95%CI: 45-59%) at 6 months, and 50% (95%CI: 43-57%) at 24 months. The Sokal and the EUTOS long-term survival (ELTS) scores failed to discriminate patients but a trend was observed for ELTS score (p=0.0547). Other variables analysed such as gender (p=0.6246), age at diagnosis (p=0.966), age at IM cessation (p=0.6197), interval diagnosis-IM (p=0.9621), interval IM initiation-DMR (p=0.9978) did not impact on the rate of relapse. In contrast, IM and DMR duration before IM cessation significantly impacted on the rate of relapse, as this interval is redundant with IM duration (p=0.008). ddPCR was applied to 174 out of 218 patients at IM cessation. A cut-off of 0.0023%IS ratio (= median of positive ratios) was also associated with a higher risk of relapse. The RFS estimate according to this cut-off is shown in Figure 1. In a multivariate analysis, the duration of IM (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified significant predictive factors with respectively p=0.0366 [HR=0.635, 95%CI: 0.415-0.972] and p=0.0081 [HR=0.635, 95%CI: 0.415-0.972)].No association was observed between a ddPCR ≥0.0023%IS and gender, Sokal or ELTS score, age at diagnosis, age at IM discontinuation, duration of IM treatment, DMR duration or the time-lapse for obtaining DMR.ConclusionWe conclude that the duration of IM and the residual leukemic cell load as determined by a sensitive technique such as ddPCR are key factors for predicting TFR for de novo CP-CML patients who have been treated with IM front-line. DisclosuresNicolini:Sun Pharma Ltd: Consultancy; BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau. Dulucq:Incyte: Consultancy; BMS: Consultancy. Etienne:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau.

Imatinib Increases Serum Creatinine by Inhibiting Its Tubular Secretion in a Reversible Fashion in Chronic Myeloid Leukemia.

Monitoring renal function is important in imatinib-treated patients with chronic myeloid leukemia because serum creatinine may increase during the course of therapy. The mechanism of this increase and its reversibility on treatment cessation have never been investigated. We retrospectively analyzed data from imatinib-treated patients explored in our renal physiology unit with measurement of glomerular filtration rate (urinary clearance of (51)CrEDTA) and of urinary clearance and tubular secretion of creatinine. Results were compared with those of controls matched for measured glomerular filtration rate, age, gender, and ethnicity. We also analyzed variations of serum creatinine before and during imatinib cessation and after imatinib resumption in patients enrolled in imatinib discontinuation studies. In 4 imatinib-treated patients who underwent thorough renal exploration, the part of creatinine clearance due to tubular secretion was negligible (2.4, 3.1, -1.3, and 2.8 mL/min) and significantly lower than that measured in their respective controls (17.7 ± 5.6, 43.0 ± 18.0, 23.1 ± 6.7, and 18.6 ± 5.6 mL/min, P < .001). In 1 patient, exploration was repeated after imatinib discontinuation and evidenced a recovery of creatinine tubular secretion (20.3 vs. 17.9 ± 5.2 mL/min in the control population, P = .2). In 15 patients of imatinib discontinuation studies, a median decrease in serum creatinine of 17.9% was observed after imatinib cessation. Resumption of treatment in 6 patients led to a median increase in serum creatinine of 18.8%. Imatinib completely blunts tubular secretion of creatinine, a previously unreported pharmacologic property. This inhibition increases serum creatinine independently of any glomerular dysfunction and is fully reversible on imatinib cessation.

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.

IMATINIB IN CHRONIC MYELOID LEUKEMIA: AN OVERVIEW

Imatinib was the first signal transduction inhibitor (STI), used in a clinical setting. It prevents a BCR-ABL protein from exerting its role in the oncogenic pathway in chronic myeloid leukemia (CML). Imatinib directly inhibits the constitutive tyrosine kinase activity. Imatinib binds to BCR-ABL kinase domain by preventing the transfer of a phosphate group to tyrosine on the protein substrate and the subsequent activation of phosphorylated protein. As the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced. The FDA has approved imatinib as first-line treatment for newly diagnosed CML in December 2002 following an International Randomized Study (IRIS), initiated in June 2000, comparing imatinib at a single daily dose 400 mg to IFN alpha plus cytarabine in newly diagnosed patients with CML in CP. Results from this study show the outstanding effectiveness of imatinib and its superiority with respect to the rates of complete hematological response (CHR), major and complete cytogenetic response (MCyR, CCyR). Patients randomized to imatinib arm at 8 – year data cut off continue to have a durable hematologic and cytogenetic responses, low progression rates to AP or BC, and remarkable survival outcomes. An overall survival (OS) rate is 85% for patients receiving imatinib (93% when only CML-related deaths and those prior to stem cell transplantation are considered). The results have been confirmed in the last years by several groups. According these cumulative results the rates of CCyR achieved after one year of therapy with imatinib at standard dose ranged from 49% to 77%, and the proportion of patients who achieved major molecular response (MMR) after one year ranged between 18% and 58%. Discontinuation of imatinib has been also tried in patients in MMR, a molecular relapse occurs in about one third of patients, generally within 6 months from imatinib cessation.

Cytokine-STATs Signalings Upregulate C/EBPβ In BCR-ABL+ Leukemic Cells Independently From BCR-ABL/JAK-STAT Pathway

Abstract Since residual chronic myelogenous leukemia (CML) stem cells may be a cause of relapse after Imatinib (IM) cessation, targeting these IM-resistant stem cells is mandatory for complete cure of this disease. CCAAT/enhancer binding protein β (C/EBPβ), a leucine zipper transcription factor, promotes both cell cycle progression and differentiation toward granulocytes in hematopoietic stem/progenitor cells under stress conditions such as infection. We have recently reported that C/EBPβ was upregulated in leukemic stem/progenitor cells derived from patients in chronic phase of CML (CP-CML) through STAT5, a major downstream target of BCR-ABL. In CML mouse model, C/EBPβ enhanced exhaustion of CML stem cells through promoting their differentiation (Hayashi Y et al, Leukemia 2013). In spite of the upregulation of C/EBPβ by BCR-ABL, CML stem cells will not be exhausted spontaneously in patients with CP-CMP. Therefore, we hypothesized that quiescent CML stem cells maintain their immature status in the bone marrow niche by suppressing C/EBPβ expression or function induced by BCR-ABL and that induction of C/EBPβ expression in CML stem cells through BCR-ABL-independent pathways may be a novel therapeutic strategy targeting CML stem cells. The aim of this study is to propose a novel therapeutic strategy that can stimulate quiescent CML stem cells with cytokine-STATs signalings and induce their exhaustion through C/EBPβ-mediated differentiation. STATs are family members of molecules which convey signals from various kinds of cytokine receptors to nucleus. In order to investigate whether STAT molecules can induce C/EBPβ expression, we first examined the effects of constitutive active (CA) form of STAT1, STAT3 and STAT5 on C/EBPβ expression in a murine hematopoietic stem cell line, EML cells. Retroviral transduction of CA-STAT5 significantly upregulated C/EBPβ mRNA and protein in EML cells. EML cells begun to differentiate toward CD11b+ myeloid lineage upon introduction of CA-STAT5. CA-STAT1 and CA-STAT3 also upregulated C/EBPβ mRNA when they were retrovirally transduced into EML cells (Figure 1). These results suggest that signaling mediated by various kinds of STATs can upregulate C/EBPβ. Consensus binding sites for STATs were not found in the proximal (∼ 4 kb) promoter region of C/EBPβ and we are currently identifying the cis-regulatory elements responsible for the STATs-dependent activation of C/EBPβ.Figure 1Figure 1. Interferon-α (IFNα) exerts STATs-mediated signaling in hematopoietic stem cells and has been used for therapy of CML. Therefore we investigated the possible involvement of C/EBPβ in efficacy of IFNα in CML treatments. Stimulation of EML cells with 500 U/ml IFNα upregulated C/EBPβ mRNA (Figure 2). Higher levels of phosphorylation of STAT1 than those of STAT3 or STAT5 were observed after stimulation with IFNα, suggesting that STAT1 mediated activation of C/EBPβ was induced by IFNα. As previously reported, C/EBPβ was upregulated in EML cells transduced with BCR-ABL (EMLBCR-ABL). Treatment of EMLBCR-ABL cells with IFNα augmented this effect significantly. IM effectively inhibited phosphorylation of STAT5 and blunted the upregulation of C/EBPβ in EMLBCR-ABL cells. Simultaneous treatment of EMLBCR-ABL cells with IFNα and IM resulted in maintained upregulation of C/EBPβ with increased phosphorylation of STAT1 and decreased phosphorylation of STAT5. These data suggested that IFNα treatment can upregulate C/EBPβ independently of signals mediated by BCR-ABL.Figure 2Figure 2. In conclusion, cytokine-STATs signalings can induce C/EBPβ expression in BCR-ABL+ leukemic cells independently from BCR-ABL/JAK-STAT pathway. Stimulations of dormant CML stem cells with cytokines might be a novel treatment strategy to eliminate these populations, leading to complete cure of CML. We are currently evaluating the in vivo effects of IFNα treatment on CML stem cells in mice models. Disclosures: No relevant conflicts of interest to declare.

Long Term Follow-Up After Imatinib Cessation For Patients Indeep Molecular Response: The Update Results Of The STIM1 Study

BackgroundImatinib treatment significantly improves survival in patients with CML. We previously demonstrated that Imatinib could be safely discontinued in pts with deep molecular response (DMR) i.e., with undetectable minimal residual disease (UMRD) of at least 2 years (Lancet oncology, 2010;11: 1029-1035).Around 40% of CML patients with stable DMR on imatinib for at least 2 years are likely to remain in a prolonged treatment-free remission (TFR) after treatment is stopped and this rate has been safely confirmed by the recent Australasian TWISTER study (Blood, 2013; 122:515-22). MethodsIn this multicenter STIM study, imatinib (of >3 years duration) was prospectively discontinued in CML pts with who were in DMR with UMRD sustained for at least 2 years (ClinicalTrials.gov,NCT00478985). The UMRD was defined with a sensitivity> to 4.5 log with ≥ 50,000 ABL transcripts amplified as internal control). Importantly, the molecular relapse 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. Beyond 2 years, molecular biology FU was performed every 3 months.In cases of molecular relapse, the treating physician was recommended to reintroduce TKI treatment. ResultsFrom July 9, 2007, to Dec 17, 2009, 100 pts (48 male, 52 female) with CML (51 pts previously treated with IFN) and a median age of 63 years (range 29–80) were recruited in the STIM trial. Eight years after the first inclusion, the median follow-up of the STIM study is now 50 months (range 9-72) with a mean of 51 months. Sixty-one patients met the definition of molecular relapse: 58 relapses occurring during the first 7 months and 3 late relapses at month 19, 20 and 22, respectively). No other molecular relapse was observed at the last update (July 2013). However, 4 extra-hematological deaths were observed: 1 case in DMR after 9 months of imatinib cessation (due to myocardial infarction) and 3 cases belonging to the molecular relapse group (due to respectively stroke, mesothelioma, and gastric carcinoma). So, considering the death in DMR without any relapse (n = 1) as a competing event the cumulative incidence of molecular relapse remains 60%. Among the 58 patients alive, we confirmed that all patients were sensitive to TKI re-challenge, and were re-treated with imatinib (n=48), nilotinib (n=5) and dasatinib (n=5). One patient stopped again for side effects. A Second attempt of TKI discontinuation was proposed for 15 patients in sustained DMR and 5 cases of molecular relapse were reported at the last update after this second attempt of TKI cessation.Among the initial 38 patients alive who are still in DMR without any treatment the median follow up is 54 months (range : 24- 71).Taking into account the cost of imatinib and the number of months without treatment in the total study population at last analysis, the savings within the STIM trial were estimated at 5.5 millions Euros. ConclusionImatinib can be safely discontinued in pts with a DMR of at least 2 years duration and we continue to recommend proposing discontinuation only in clinical trials with close molecular monitoring. In spite of the fact that we did not observed other molecular relapse beyond 2 years a long-term follow-up of the different cessation studies will be necessary to affirm cure. Because the life expectancy of de novo CML is now closed to the healthy population, the long-term medical costs and quality of life have become very important and depend on the possibility to cease safety TKI in long term. Disclosures:Rea:Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Etienne:novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Rousselot:BMS, Ariad, Pfizer: Honoraria from BMS, Ariad, Pfizer. Grants from BMS Other.

Preliminary Report Of The STIM2 Study: A Multicenter Stop Imatinib Trial For Chronic Phase Chronic Myeloid Leukemia De Novo Patients On Imatinib

BackgroundIn the Stop imatinib study (STIM)1, we previously demonstrated that Imatinib could be safely discontinued in patients with a sustained deep molecular response (DMR) (undetectable BCR-ABLtranscripts (UMRD) for at least 2 years) (Lancet oncology, 2010;11: 1029-1035). Recently, these results were confirmed by the Australasian TWISTER study using criteria of imatinib cessation very similar to those used in the STIM1 study (Blood, 2013; 122:515-22). However in the both studies, half of the patients were previously treated with IFN leading to a non-homogenous cohort of patients. So we conducted prospectively a second trial (STIM2) where cessation of imatinib treatment was proposed for patients in sustained DMR who were treated only with imatinib. MethodsIn this new multicenter, non-randomized STIM2 study (ClinicalTrials.gov, NCT01343173), imatinib was discontinued in CML pts with the same criteria as those we reported previously for the STIM1 i.e. sustained DMR defined as remission lasting more than 2 consecutive years and confirmed on five datapoints of BCR–ABL analyses by quantitative RT-PCR during these 2 years. The UMRD was defined with a sensitivity> to 4.5 log with ≥ 50.000 ABL transcripts amplified as internal control. The molecular relapse 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, on 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. Beyond 2 years, molecular biology FU was performed every 3 months. ResultsFrom April 2011 to June 2013, 124 CML pts were included (62 men,62 women) with a median age of 61 years recruited in the 23 French centers. At the last update, the median follow up of the first 124 pts enrolled is 12 months (range 1-25). After discontinuation of imatinib, a molecular relapse occurred in 48 pts (45 relapses during the first 6 months and 3 relapses between 6 and 12 month), and 76 patients were still free of treatment at the last update with DMR. However 41 experienced a BCR-ABL RQ-PCR fluctuation without clear molecular relapse. In this so-called-fluctuation group of patients, 7 were found positive once, 6 twice, 12 patients between 3 and 5 times, 10 patients between 6 and 10 times and 6 patients more than 10 times confirming that BCR-ABL reappearance does not mean automatically clinical relapse.We confirmed also that all patients were sensitive to a TKI re-challenge. Actually, 33 patients were retreated with imatinib 5 with nilotinib and 3 with dasatinib. The median time to achieve again a CMR from the molecular relapse was 7 months (range 4-16 months) and from re-initiation of TKI was 4 months (range 2-14). Taking into account the cost of imatinib and the number of months without treatment in the total study population at last analysis, the savings within the STIM2 trial were estimated at 2.8 millions Euros. ConclusionWe confirm that Imatinib can be safely and prospectively discontinued in pts with DMR of at least 2 years duration in patients only treated with imatinib. To stop treatment it may not require the complete eradication of residual leukemic stem cells since positive fluctuation PCR results do not lead to CML relapse or progression. These intriguing results, even for imatinib treated patients since disease onset (already observed after IFN therapy), are comparable to those reported with the more sensitive PCR on DNA in the TWISTER study and are under investigations in our laboratory. Disclosures:Mahon:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Nicolini:Novartis, Ariad, Teva, BMS and Pfizer: Honoraria from Novartis, Ariad, Teva, BMS and Pfizer. Grants from Novartis. Other. Rea:Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Etienne:novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees.

Imatinib cessation in children and adolescents with chronic myeloid leukemia in chronic phase

Imatinib can be safely discontinued in adults with chronic myeloid leukemia (CML) where there is a prolonged complete molecular response (CMR). No data are available in the pediatric population. Six children with CML discontinued imatinib by themselves. Only three of them were in CMR but for <2 years. A significant increase in transcript level was observed in all six patients after cessation of imatinib and five patients lost the major molecular response (MMR). Four patients regained the MMR within 3 months. Cessation of imatinib in children is not recommended outside a trial, particularly in patients without prolonged CMR.

Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study

AbstractMost patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months, the actuarial estimate of stable treatment-free remission was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib, a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up, 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse.

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.

Activation Levels of Natural Killer Cells and CD8+ T Cells Correlate Highly with Sustained Complete Molecular Response After Discontinuation of Imatinib in Chronic Myeloid Leukemia Patients

AbstractAbstract 3745 Introduction:Recently, it has been recognized that some chronic myeloid leukemia (CML) patients with a complete molecular response (CMR) are able to maintain the CMR after discontinuation of imatinib. Mahon et al. reported that among patients with a CMR lasting at least 2 years, CMR was sustained in 41% after discontinuation of imatinib (Lancet Oncol. 2010;11:1029). Similarly, Takahashi et al. reported that 47% of Japanese CML patients with CMR maintained CMR after imatinib discontinuation (Haematologica 2012;97:903). Moreover, Ohyashiki et al. have recently demonstrated that higher peripheral natural killer (NK) cell counts are associated with a reduced risk of relapse after halting imatinib (Br. J. Haematol. 2012;157:254). These findings suggest that, although CML stem cells may remain, even if CMR status is attained, some CML patients could discontinue imatinib therapy and maintain a stable condition, possibly owing to immune surveillance. Aim:To more precisely identify these patients who can safely discontinue imatinib, we characterized the immunophenotype profiles of CML patients. We compared the profiles among CML patients who received imatinib with CMR for more than 2 consecutive years (CMR group), those who could not sustain CMR but maintained a major molecular response (fluctuated CMR group), those who sustained CMR for more than 6 months after discontinuation of imatinib (STIM group), those who relapsed after discontinuation of imatinib (relapse group), and healthy volunteers (control group). Methods:Peripheral blood mononuclear cells (PBMCs) from CML patients and healthy volunteers were separated using a Ficoll density gradient, and immunophenotyping analysis was performed with a 5-color flow cytometry panel, including antibodies against the following cell surface antigens and effector molecules: CD3, CD8, CD45RO, CD56, CCR7, IFN-g, granzyme B, and perforin. After PBMCs were stimulated with phorbol 12-myristate 13-acetate and ionomycin for 4 h in the presence of monensin, cell surface antigens were stained, fixed, and permeabilized. Resultant cells were then intracellularly stained and analyzed with the FACSCanto II flow cytometer. Results:The percentage of effector populations of NK cells, such as interferon (IFN)-g+CD3−CD56+ cells, was significantly higher in the CMR and STIM groups than in the control group. In contrast, the percentage of effector populations of CD8+ T cells, such as IFN-g+CD8+ T cells, was significantly higher in the STIM and control groups than in the CMR group. Moreover, the percentage of effector populations of NK cells, but not CD8+ T cells, was significantly higher in the CMR group than in the fluctuated CMR group. On the other hand, CML patients with a lower percentage of effector populations of NK cells and CD8+T cells, and those with a higher percentage of these effector populations, but whose percentage had decreased after imatinib cessation, had a tendency to relapse after discontinuation of imatinib. Conclusion:The percentage of effector populations of NK cells and CD8+ T cells, such as those expressing IFN-g, correlated highly with sustained CMR after discontinuation of imatinib. Moreover, the activation level of NK cells, but not CD8+ T cells, inversely correlated with the BCR-ABL1 transcript level. Taken together, these results suggest that whether imatinib treatment can be safely discontinued may depend greatly on the immunological activation status of both NK cells and CD8+ T cells in CML patients. Disclosures:No relevant conflicts of interest to declare.

Early Molecular Response and Female Sex Strongly Predict Achievement of Stable Undetectable BCR-ABL1, a Criterion for Imatinib Discontinuation in Patients with CML

AbstractAbstract 165▪▪This icon denotes a clinically relevant abstract Introduction.The opportunity to discontinue kinase inhibitor therapy while maintaining a deep remission is desirable for many CML patients. Despite good responses to imatinib for most patients, treatment related side effects remain problematic and can affect quality of life. Studies have demonstrated that a proportion of carefully selected patients can sustain response after imatinib discontinuation. The first requirement for successful discontinuation is likely to be stable deep molecular response based on a sensitive RQ-PCR assay. The criteria for patient selection in the French Stop Imatinib (STIM) and Australian CML8 (TWISTER) imatinib discontinuation trials included stable undetectable BCR-ABL1 transcripts for at least 24 months with a PCR sensitivity of 5 and 4.5 log, respectively. The probability of continued remission after discontinuation for imatinib treated patients without prior interferon-α therapy was approximately 33%. It is not known how many imatinib treated patients will eventually meet these PCR criteria for a discontinuation trial. Aims.We aimed to determine 1) the cumulative probability of achieving the PCR criteria for imatinib discontinuation as defined in the CML8 study, and 2) factors that predicted its achievement. Method.The molecular response of 415 de-novo CML patients in chronic phase enrolled in consecutive clinical trials of imatinib since July 2000 was examined. The assigned daily imatinib dose was 400 mg for 90 patients, 600 mg for 202 patients and 800 mg for 123 patients. Molecular data were included until imatinib cessation or last follow-up. The minimum time since commencing imatinib was 30 months and the median time on imatinib was 45 months, range 3 to 136. The CML8 PCR criteria for imatinib discontinuation were confirmed undetectable BCR-ABL1 transcripts at a sensitivity of 4.5 log that remained undetectable on all PCR tests for at least 24 months while on imatinib therapy. In the current analysis the CML8 PCR discontinuation criteria are defined as ‘stable UMR4.5’. Results.At 8 years of imatinib therapy the cumulative incidence of stable UMR4.5 was 43%, Figure A. Patients were divided into groups according to the time to a confirmed major molecular response (MMR): by 3, 6, 12 or 18 months. There was a significant difference in stable UMR4.5, P<.001, Figure B. The cumulative incidence of stable UMR4.5 was more than 60% for all patients who achieved MMR by 12 months and only 16% for patients with MMR between 12 and 18 months. The time to a confirmed MMR influenced the time to reach a stable UMR4.5 after achieving MMR. Considering only patients who achieved stable UMR4.5, patients achieving MMR by 3 months took a further 39 months (median) to achieve stable UMR4.5. For those with MMR by 6 months and 12 months, the median month to a stable UMR4.5 was 50 and 76 months after MMR, P<.001. This suggests slower dynamics of BCR-ABL1 decline with delayed time to MMR. 52 patients achieved MMR after 18 months and none achieved a stable UMR4.5 by 8 years: median time to MMR was 27 months, range 21–87. Factors at the time of commencing imatinib (baseline) were examined for their association with stable UMR4.5; Sokal risk, age, sex, assigned imatinib dose and baseline BCR-ABL1 value, as well as the 3 month BCR-ABL1 value. Quantitative factors were categorized into groups, with cut-offs set at the median for age and quartiles for the baseline BCR-ABL1 value. By univariate analysis the only baseline factor that predicted for higher cumulative incidence of stable UMR4.5 at 8 years was female versus male, 68% versus 30%, P<.001, Figure C. During imatinib therapy females had significantly lower median BCR-ABL1 values at every assessment up to 42 months. The 3 month BCR-ABL1 value also predicted stable UMR4.5, P<.001, Figure D. Baseline and 3 month factors were entered into a multivariate analysis. The 3 month BCR-ABL1 value and sex were independent predictors of stable UMR4.5, P=.004 and P=.005, respectively. Conclusion.The time to achieve an MMR, sex and the 3 month BCR-ABL1 value predicted stable undetectable BCR-ABL1 while on imatinib. Lower BCR-ABL1 values and higher rates of stable UMR4.5 in females could be related to better drug adherence or biological differences. Further studies are indicated. Early MMR led to early achievement of the discontinuation criteria. The findings justify the focus on early achievement of MMR as a strategy to maximize recruitment to discontinuation studies. [Display omitted] Disclosures:Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy. Ross:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Yeung:Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hughes:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding.

Treatment of recurrent or metastatic gastrointestinal stromal tumor: surgery or not

Currently, the treatment of recurrent or metastatic gastrointestinal stromal tumor(GIST) has become a tremendous challenge. Some international clinical trials revealed that imatinib might significantly improve the survival of patients with recurrent or metastatic GIST. Though the combination of surgery and imatinib has become an ideal treatment of metastatic GIST, there still exist some controversies regarding how to combine the two methods. Imatinib may influence the blood coagulation mechanism, therefore it is suggested that imatinib cessation should be performed a week before operation. Cytoreductive surgery has some clinical effects on recurrent or metastatic GIST, which can be combined with targeted therapy. Furthermore, the clinical trial for recurrent or metastatic GIST needs further evaluation.