ALBERT

Description: Background : Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up. Methods : Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS 〉0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)). Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively. Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1). Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)). Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p

Description: Abstract 2759 BACKGROUND Nilotinib, a highly potent, selective inhibitor of BCR-ABL, is now approved for frontline treatment of Philadelphia chromosome positive (Ph+) CP CML. ENEST1st (Evaluating Nilotinib Efficacy and Safety trial as first line treatment) is a phase IIIb, open-label study of nilotinib in adult patients with newly diagnosed CP CML (ClinicalTrials.gov NCT01061177). The primary study aim is to establish the rate of molecular remission with a sensitivity of 4 log (MR4) rate through EUTOS (European Treatment and Outcomes Study) laboratories to improve the sensitivity and standardisation of RT-PCR for low level BCR-ABL detection and further refine the working definition of deep molecular response. The attainment of sustained MR4 will identify a patient population potentially eligible to join studies of tyrosine kinase inhibitor discontinuation in CP CML. METHODS 806 patients (pts) with newly diagnosed BCR-ABL+ CML-CP, diagnosed within 6 months, were to be treated with nilotinib 300 mg BID for a study period of 24 months. The primary study endpoint is MR4 rate at 18 months, initially defined as undetectable BCR-ABL transcripts by quantitative RT- PCR in a peripheral blood sample of at least 10 ml with a minimum sensitivity of 1:10,000. Molecular monitoring was performed by 13 EUTOS laboratories with conversion factors to the International Scale to facilitate standardised measurement. Key secondary endpoints include: rate of progressions to accelerated phase (AP) or blast crisis (BC) in year 1 and 2; rate of events in patients achieving MR4 at 1 year; rate of MMR (

Description: Most CML patients are sensitive to Imatinib Mesylate (IM), however, a small fraction develop resistance, mostly through the onset of BCR-ABL mutations. More than 30 mutations have been described, mostly in advanced phase, and confer different levels of clinical resistance. In this setting, clinical trials with 2nd generation tyrosine kinase inhibitors (TKI) provide encouraging results, however neither in vitro nor clinical activity has been demonstrated when the most frequent BCR-ABL mutation, T315I, has been identified. In this retrospective study from 5 French centers, we analysed the features and clinical outcomes of 27 CML patients treated with IM and presenting either clinical, cytological, cytogenetic resistance or molecular progression, and harboring a BCR-ABLT315I mutation detected by direct sequencing (same method in the 5 different laboratories, quality control exchanges). The 27 patients were in chronic phase (CP) at diagnosis, with 17 M and 10 F with a median age at diagnosis of 52 (25–70). Sokal scores were high for 8 pts, intermediate for 6 pts, low for 3 pts and unknown for 8, 2 were in blast crisis (BC) at CML diagnosis. Transcripts were M-BCR for 22 patients and m-BCR for 2 patients and unknown for 3 pts. At diagnosis 4 pts had additional chromosomal abnormalities as a variant Ph1 chromosome, a -7, a -Y, and an additional t(3;7;12) to the Ph1. Progression has been defined as a 2-fold rise in BCR-ABL transcripts levels, loss of any previous response to IM, and a transition towards a more advanced phase of the disease. At T315I discovery, 11 pts were in CP, 4 in accelerated phase, and a majority in BC [7 in myeloid and 5 in lymphoid]. The median interval between diagnosis and IM was 20 Mo. (0–145.2). The median initial dose of IM was 464 mg/day. Most of the patients were poor responders to IM of which 12 pts that obtained no more than a CHR, 2 pts a PCyR, 7 pts a CcyR, 2 pts a MMR, 1 pt no response, and 3 unknown. Twenty-one pts harboured a T315I alone, 1 a T315I with a Y253H, 2 with a M351T, 1 with a E255K+E255V, 1 with a L324Q, and 1 with a F311L, with no impact on survival. The median time for progression from day 1 IM was short [13 Mo. (0–49.6)] regardless of the phase of the disease at T315I identification, and the median interval IM start-T315I identification was 20 Mo. (0–57.6). Median overall survival from D1 of IM was 17.5 Mo. for advanced phases and 42.5 Mo. for CP (p=0.08). All patients progressed with no difference for time to progression between phases (p〉0.05). Figure Figure Neither additional mutations (p=0.91), nor additional chromosomal abnormalities (p=0.11), nor Dasatinib treatment (p=0.15) modified overall survival. In conclusion, the onset of BCR-ABLT315I mutations occurs preferentially in high-risk CML, seems more frequent in advanced phases, and is always responsible for progression and poor survival, underlying the need for alternative treatments, in patients lacking a histocompatible donor.

Description: Background Recent data indicate that the survival of chronic myeloid leukemia (CML) patients, who are in Major Molecular Response with TKI, is not statistically significantly different from that of the general population and that a subgroup of patients who experienced long-term Complete Molecular Responses can stop therapy without relapse. However, less is known regarding the actual impact of TKI therapies or their cessation on patients’ health-related quality of life (HRQoL). Aim We conducted a monocentric observational quality of life study on CML patients having received or currently receiving Imatinib, Nilotinb or Dasatinib, in order to investigate the relationships between HRQoL and treatment or treatment interruption. Patients and Methods The analysis was performed on 110 CML patients diagnosed and recruited from 1999 to 2012 in our department and followed for more than 3 months. At the time of HRQoL assessment (median duration from diagnosis: 5.6 years; interquartile range [IQR] 2.4-10.1), 8.8% of patients had stopped TKI therapy for more than 3 months because of long-time CMR, 49.6% were treated with Imatinib, 22.1% with Dasatinib and 19.5% with Nilotinib. The total number of different prescribed TKIs in the course of the disease was 1 in 60.2% of the cases, 2 in 23% and 3 in 16.8%. HRQoL was assessed with the 36-Item Short-Form Health Survey (SF-36), using age-sex adjusted standardized scores expressed as standard deviation [SD] from the French general population reference values for age and gender. Key socio-demographic and clinical data including age, gender, education, Sokal risk, response to therapy and duration of treatment, smoking, obesity, hypertension, diabetes, dyslipidemia, number of medications, ECOG performance status, ADL/IADL and Mini Nutritional Assessment scale (MNA) were also taken into account. Univariate and multivariate linear regression analyses were used to identify independent predictors for each SF-36 subscale and summary scores (Physical [PCS] and Mental Composite Scores [MCS]). Results In univariate analysis, factors significantly associated with lower PCS scores included younger age (under 45) (-1.20 SD), lower education level (-0.79SD), obesity (BMI〉30) (-1.39SD), pre-existence of dyslipidemia (-1.57SD), ADL with more than 1 limitation (-0.98SD), ECOG 〉1 (-1.83SD), MNA at risk or poor nutritional status (-1.26SD); factors associated with lower MCS scores were pre-existence of dyslipidemia (-0.92SD), ECOG〉1 (-1.31SD), MNA (-0.87SD), current CML treatment (-0.28SD [Imatinib],-0.42SD [Sprycel] and -0.53SD [Nilotinib]) and more than 2 lines of TKI (-0.89SD). In multivariate analysis, only younger age (p=0.009) and dyslipidemia (p=0.023) were negatively correlated to PCS and current CML treatment (p=0.001) and more than 2 TKI (p=0.013) negatively correlated to MCS. In figure 1, we report the standardized SF-36 scores of CML patients according to age (1a), treatment (1b) or treatment lines (1c). Conclusion We confirm previous data indicating worse HRQoL in younger CML patients treated with Imatinib. In our study, this effect was also observed with 2nd-generation TKIs. Our findings were in the same order of magnitude as previously reported (Efficace et al, blood, 2011). We failed to demonstrate any major differential effect between the different TKI (Imatinib, Nilotinib or Dasatinib) on HRQoL suggesting that the choice of TKI therapy cannot be determined by this criterion. Moreover, comparing the number of TKI changes, we failed to demonstrate any effect of “only-one” change of TKI on HRQoL,. This suggests that one change in CML therapy does not worsen QOL , whereas a drastic decrease in mental HRQoL scores was found in patients receiving more than two lines of TKI. The most relevant finding was that patients who benefited from TKI interruption because of stable complete molecular remission had better mental HRQoL outcomes, suggesting that TKI interruption could have a positive impact on HRQoL and hence has to become the objective to achieve in CML to normalize HRQoL. Disclosures: Giraudier: NOvartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria. Tulliez:Novartis: Consultancy, Honoraria.

Description: Key Points First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with deep and long-lasting molecular responses. A suboptimal response or resistance prior to dasatinib or nilotinib is associated with significantly worse treatment-free remission.

Description: Abstract 3293 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of Ph+ CML patients (pts) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study, which is a Phase IIIb, open label, multicenter study, was initiated to obtain additional efficacy and safety information in pts with imatinib-resistant or -intolerant CML in CML-CP, CML-AP, or blast crisis (BC) in a clinical practice setting outside of a registration program. Methods: Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Cytogenetic and hematological responses were provided by investigator assessment and monitored according to the current European Leukemia Network (ELN) recommendations. Safety assessments included monitoring for all adverse events (AEs), serious AEs and cardiac procedures. A centralized approach to molecular testing in France facilitated matching of the PCR results to ENACT pts who were monitored for molecular response as a standard of care. BCR-ABL/ABL ratio (in %) were reported on the international scale (IS), French physicians followed the current ELN recommendations and monitored pts by PCR at baseline and every 3 months thereafter. Major molecular response (MMR) was defined as IS ≤ 0.1%. In addition, pts with ≤ 0.003% IS are reported. Confirmed loss of MMR was defined as IS 〉 0.1% on two consecutive PCR tests in pts previously in MMR Results: A total of 168 French CML-CP pts enrolled in the ENACT study between Jan. 2006 and Oct. 2008 with molecular response data available for 77% of pts. The median age of pts was 57 years, 56% were imatinib-resistant and 43% were imatinib-intolerant as determined by physician assessment. At study completion, 108 (64%) pts were continuing on nilotinib. The main reasons for treatment discontinuation were unsatisfactory therapeutic effect and AEs (16% for both). Median (range) duration of nilotinib exposure was 363 (4–765) days; median (range) average dose intensity was 793 (222–913) mg/day. Dose interruptions and reductions lasting longer than 5 days occurred in 36.9% and 11.9% of pts, respectively, with AEs being the main reason. The majority of nilotinib-related grade 3/4 AEs were hematologic, with thrombocytopenia (22.6%) and neutropenia (14.9%) being the most common. Non-hematologic AEs were mostly grade 1/2, not study drug-related and included fatigue, headache and rash. No incidence of grade 3/4 QT prolongation (QTcF 〉 500 msec) was observed and no pts experienced study drug-related grade 3/4 pancreatitis or pleural effusion on study. Overall major cytogenetic response (MCyR) and complete hematologic response (CHR) rates were both 54%, which are higher than those observed in the overall ENACT CML-CP cohort at 45% and 43%, respectively. Among the pts with molecular response data, 10 (7.8%) came to the study with MMR, one had a confirmed loss of MMR but subsequently regained MMR. The proportion of pts with post-baseline MMR (regardless of baseline response) was 42% (55 pts); 38% of pts achieved an MMR on study. The proportion of pts with a post-baseline ratio ≤ 0.003% IS was 16% (21 pts). The achieved molecular responses were durable with only 4 pts with confirmed loss of MMR, while another 3 pts met the criteria for loss of response but subsequently regained MMR. Of the 61 pts with CCyR and molecular data available, 72% also achieved MMR (see Table). Conclusions: This analysis of the French CML-CP subset of a large expanded access study further demonstrates that nilotinib is well tolerated and effective in heavily pretreated pts with CML-CP. A majority of pts (72%) with CCyR also had MMR. This data supports the use of nilotinib at 400 mg bid as the recommended dose in French pts. Disclosures: Nicolini: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Bordessoule:Novartis Pharmaceuticals: Honoraria. Belanger:Novartis Pharmaceuticals: Employment. Lamy:Novartis Pharmaceuticals: Honoraria. Gardembas-Pain:Novartis Pharmaceuticals: Honoraria. Maloisel:Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Calgene: Research Funding. Rea:Novartis Pharmaceuticals: Honoraria. Johnson-Ansah:Novartis: Consultancy. Lenain:Novartis Pharmaceuticals: Honoraria. Szczudlo:Novartis: Employment. Wang:Novartis Pharmaceuticals: Employment. Duh:Novartis Pharmaceuticals: Research Funding.

Description: Abstract 4261 Molecular monitoring of chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors (TKI) is essential for therapeutic stratification. In this context inter-laboratory reproducibility is mandatory. This requires standardization and strict alignment to international scale (IS), as established by the IRIS laboratories. We compared economic and analytical performances, including the possibility of reporting results on the international scale, of an automated cartridge-based assay (Xpert BCR-ABL MonitorTM, Cepheid) to classical non-automated analysis on 181 blood samples from TKI treated CML patients in up to three experienced laboratories. The automated Xpert BCR-ABL MonitorTM assay greatly improved reproducibility between non standardized laboratories. Reproducible sensitivity covered 5 logs, on condition that pre-analytical delays were less than 6 hours. Results were convertible to the international reporting scale. Assessment of average costs showed that this automated assay could be economically relevant for annual activity levels below 300, although cost stability was achieved at 600, compared to 1200 annual tests for non-automated testing. The Xpert BCR-ABL MonitorTM assay could therefore be used in local laboratories for routine quantification of e13/e14-a2 transcripts and might contribute to simplified standardization. However, its prognostic impact relative to non-automated quantification remains to be tested prospectively within appropriate clinical trials. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 604FN2 Background: Imatinib, the first tyrosine kinase inhibitor (TKI) directed against the Bcr-Abl oncoprotein, has dramatically improved outcomes for pts with CML. Dasatinib and nilotinib, 2 highly potent second generation (2G)-TKI, have been historically licensed for the treatment of pts with resistance or intolerance to imatinib. They have recently received approval in the frontline setting in chronic phase (CP)-CML. Despite the outstanding efficacy of these drugs, their curative potential remains uncertain. Most TKI-treated pts retain residual leukemic cells detected by means of RTQ-PCR and termination of TKI therapy under such circumstances usually leads to disease relapse. Consequently, it is believed that most CML pts require a lifelong TKI treatment. On the contrary, stopping TKI may be envisaged in pts with stable undetectable molecular residual disease (UMRD), as suggested by recent results from the STop IMatinib trial (Mahon et al. Lancet Oncol. 2010), and our observation that dasatinib could be safely stopped in a pt with a stable UMRD suffering from drug-induced pleural effusion (Cony-Makhoul, et al. unpublished). Aims: We asked whether 2G-TKI could be ceased in CML pts with a stable UMRD. The primary objective of our work was to evaluate the risk of loosing major molecular responses (MMR: BCR-ABL/ABL internationally standardized (IS) ratio ≤ 0.1%) by 6 months. Methods: Pts aged at least 18 years with CP-CML and UMRD were proposed dasatinib or nilotinib discontinuation provided that (1) no prior progression to accelerated phase or blast crisis occurred (2) UMRD was sustained on continuing therapy. UMRD was defined by undetectable Bcr-Abl using internationally standardized RTQ-PCR testing performed in local laboratories, providing that at least 20 000 copies of the control gene had been amplified. After 2G-TKI discontinuation, Bcr-Abl transcripts were quantified monthly during the first 6 months and every 2 to 3 months thereafter. Dasatinib or nilotinib were advised to be re-introduced upon loss of MMR. Results: As of August 1, 2011, 25 pts agreed to stop therapy. The results presented here focus on the subgroup of 16 pts with a minimum follow-up (FU) of 6 months (median 15, range: 7–21). These were 9 females and 7 males, with a median age of 59 years (34-81). The Sokal risk group was low in 11/16 (68.75%), intermediate in 2/16 (12.5%), high in 1/16 (6.25%) and unknown in 2/16 (12.5%). Dasatinib (n=9) or nilotinib (n=7) had been administered owing to imatinib grade 2 hematologic or grade 2 to 4 non hematologic intolerance (n=13), secondary imatinib resistance (n=1) or as the frontline drug (n=1). At start of 2G-TKI, 1 pt was in CP, 1 had a complete hematologic response only, 2 had a partial cytogenetic response, 3 had a complete cytogenetic response but lacked MMR, 4 had a MMR with detectable Bcr-Abl transcripts and 5 had a UMRD. The median time on 2G-TKI therapy prior to discontinuation was 32 months (21-56). The median duration of sustained UMRD was 27 months (21-64). Subsequently, MMR was lost in 31.25% (5/16) pts after a median time off-therapy of 4 months (1-5). Treatment was restarted in 4 of these and in an additional pt without MMR loss but showing a detectable MRD on 2 consecutive assessments. Both MMR and UMRD were rapidly regained upon 2G-TKI re-introduction. Eleven pts remained off-therapy at the last follow-up after a median of 13 months (7-20), among which 10 with either a stable UMRD or weakly detectable Bcr-Abl transcripts on one or more occasions. Gender, age, Sokal risk group, type of 2G-TKI, total duration of continuous TKI treatment, duration of 2G-TKI therapy and of UMRD prior to treatment discontinuation did not markedly differ between pts who lost MMR and those with treatment-free persistent MMR but these results may be taken with caution due to the small size of our cohort. Conclusion: 2G-TKI may be safely discontinued in CML pts with a long-lasting UMRD under strict molecular monitoring conditions. Importantly, the emergence of a low level of detectable residual disease below the MMR threshold after 2G-TKI withdrawal may not automatically herald CML relapse and may not preclude the possibility to remain treatment-free. A longer follow-up is required to ascertain whether CML will recur. Our study provides a reasonable basis for subsequent large scale prospective trials. Updated results based on a minimal 6 month-FU of the whole cohort will be presented. Disclosures: Rea: Novartis, BMS: Membership on an entity's Board of Directors or advisory committees. Nicolini:Norvartis Pharma France: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb France: Consultancy, Speakers Bureau. Tulliez:Novartis: clinical trial investigator. Guilhot:Novartis, BMS: Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis, BMS: Membership on an entity's Board of Directors or advisory committees.