Suboptimal Molecular Response Research Articles

Abstract 4728: IFNγ signaling drives EZH2 degradation to induce MHC-II expression in melanoma

Abstract Background: The molecular mechanisms governing anti-PD-1 resistance in melanoma are not fully understood. Suboptimal transcriptional and molecular response to interferon-gamma (IFNγ) is commonly identified in tumors with intrinsic or acquired resistance to anti-PD-1. Epigenetic regulators have been shown to reprogram IFNγ responses in some cases, though the mechanism is not clear. The ability of melanoma cells to express MHC-II is a positive clinical predictor to anti-PD-1 therapy, and MHC-II is induced only on cells with robust IFNγ responses. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator with both methyltransferase-dependent and -independent function, can suppress IFNγ target genes and is frequently overexpressed in melanoma. However, the mechanisms whereby EZH2 interacts with the IFNγ pathway and its role in melanoma-specific MHC-II expression is not known. Methods: HLA-DR (MHC-II)-proficient (A375, SKMEL28 and SKMEL5) and -deficient (CHL-1 and MEWO) melanoma cell lines were stimulated with IFNγ for up to 48h, and the modulation of EZH2 protein and function were studied temporally. To test the role of EZH2 in MHC-II (HLA-DR) expression in IFNγ responses, genetic (siRNA) and chemical (GSK343) EZH2 inhibition was utilized. Results: EZH2 was highly expressed in all cell lines tested, regardless of HLA-DR-proficiency. In 2 out of 3 HLA-DR-inducible melanoma cell lines, EZH2 protein expression was downregulated (4-24 hrs) in response to IFNγ stimulation, without effects on EZH2 mRNA expression or downstream tri-methylated H3K27 expression. Blocking proteosomal degradation with MG-132 reversed the IFNγ-induced decrease in EZH2 expression in HLA-DR-proficient cell lines. After siRNA knockdown of EZH2, SKMEL28 cells increased constitutive HLA-DR expression, while A375 cells became more sensitive to IFNγ-induced HLA-DR upregulation. In addition, IFNγ-induced HLA-DR was increased in A375 cells with EZH2 inhibition using GSK343. Conclusion: This work demonstrates a potential role for EZH2 in suppressing IFNγ responses, including the induction of MHC-II, in melanoma cells. EZH2 is subject to proteosomal degradation in MHC-II-inducible cell lines, which, in part, contributes to the expression of MHC-II. Citation Format: Jamaal L. James, Susan R. Opalenik, Abigail Toren, Rebecca S. Cook, Justin M. Balko. IFNγ signaling drives EZH2 degradation to induce MHC-II expression in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4728.

Effect of Imatinib on Bone Marrow Morphology and Angiogenesis in Chronic Myeloid Leukemia.

Background and Objectives Chronic myeloid leukemia (CML) is characterized by hyperproliferation of myeloid precursors, increased fibrosis, and neoangiogenesis in the bone marrow. Imatinib inhibits BCR-ABL tyrosine kinase produced due to reciprocal translocation t(9;22) in neoplastic CML cells. It reduces hyperproliferation of myeloid precursors and has been found to affect bone marrow fibrosis and angiogenesis. This study was done to assess the effect of imatinib on bone marrow morphology and angiogenesis in CML. Methods 31 newly diagnosed CML patients were evaluated before and after 3 months of imatinib therapy. A marrow morphological response (MMR) score was used to assess marrow cytological and histological features including grade of fibrosis. Mean microvessel density (MVD) was also assessed. Hematological parameters and BCR-ABL transcript levels were assessed in the peripheral blood. Results 86.21% of patients showed decrease in marrow cellularity with normalization of M:E ratio. 72.42% of patients had decrease in grade of fibrosis and 17.24% showed no change while 10.34% of patients showed progression of fibrosis grade. Patients with MMR score ≥ 2 (n=4) and those with progression of fibrosis grade (n=3) showed suboptimal molecular response (BCR-ABL transcripts > 10%). Pretherapy mean MVD of patients (14.69 ± 5.28) was higher than that of controls (6.32 ± 1.64). A significant reduction of 66.51% was observed in posttherapy mean MVD (4.98 ± 2.77) of CML patients (p<0.001). Conclusion Imatinib therapy in CML not only decreases marrow cellularity, but also helps towards normalization of bone marrow microenvironment by reducing fibrosis and angiogenesis.

Spirit 2: Final 5 Year Analysis of the UK National Cancer Research Institute Randomized Study Comparing Imatinib with Dasatinib in Patients with Newly Diagnosed Chronic Phase CML

▪Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib (I) 400mg with dasatinib (D) 100mg daily in newly diagnosed chronic phase CML. The primary endpoint was 5 year event-free survival. Methods. 812 (406 in each arm) of 814 patients recruited started study medication (median age 53.2, 275/812 (33.8%) were over 60 years old). Patients were recruited at 144 hospitals between August 2008 and March 2013 and randomized to receive either imatinib 400mg or dasatinib 100mg daily. Secondary endpoints included overall survival, rates of treatment failure, cytogenetic/molecular response - RT-PCR BCR-ABL/ABL ratio of <0.1%IS(major molecular response (MMR), 3 log reduction, MR3) and deeper. To address the potential confounding effect on the primary endpoint of patients switching from randomized treatment to an alternative TKI or other treatment, exploratory per-protocol analyses were performed using the inverse probability of censoring weighting (IPCW) method.Results. All patients have now completed 5 years of follow-up. 424/812 (52.2%) patients completed the study whilst still taking first line medication: 230/406 (56.7%) on dasatinib, 194/406 (47.8%) on imatinib. Of the patients who discontinued first line therapy, more patients on the imatinib arm switched due to suboptimal PCR response (as decided by the local investigator) than on dasatinib (D7/406, 1.7%; I71/406, 17.4%) but more patients on the dasatinib arm discontinued due to intolerance (D123/406, 30.3%; I68/406, 16.7%). More patients went on to transplant in the imatinib arm than in the dasatinib arm (D 6/406, 1.5%; I 30/406 7.6%) and in the imatinib patients undergoing transplant the reason for first line treatment failure was disease progression in 5/30 and suboptimal molecular response in 11/30. Using an intention to treat analysis cumulative incidence of MR3 and MR4 on first line therapy within 5 years was higher in the dasatinib arm than the imatinib arm (MR3: D 83.0%, I 63.0% - difference 20.0%, p<0.0001; MR4: D 77.5%, I 57.2% - difference 20.3%, p<0.0001).At 24 months the complete cytogenetic response rate was D 42.6%, I 31.8% - difference 10.8%, Chi-square test p=0.001.At 5 years the probability of treatment failure-free survival was higher with dasatinib than imatinib(D60.9%, I52.9% - HR: 0.73 (95%-CI:0.59-0.90), p=0.004) but there were no significant differences in event free survival (D91.0%, I89.0% - HR:0.80 (95%-CI:0.51-1.25), p=0.319) or overall survival (D91.9%, I91.2% - HR: 0.90 (95%-CI:0.56-1.47), p=0.690). IPCW modelling results will be presented at the meeting.The overall rate of pleural effusion over 5 years in the dasatinib arm was 36.0% with a higher incidence in older patients. 13 patients developed their first pleural effusion after 3 years on study. Conclusions. In SPIRIT 2 we observed a higher molecular and cytogenetic response rate and also a higher pleural effusion rate with dasatinib but a higher treatment failure rate with imatinib often because investigators were concerned about sub-optimal PCR responses. More imatinib-treated patients proceeded to transplant. There were no statistically significant differences in event free survival (the primary endpoint) or overall survival. Imatinib remains a highly effective first line therapy though subgroup analyses are planned to explore whether dasatinib may have advantages in particular clinical scenarios. DisclosuresO'Brien:Bristol Myers Squibb: Research Funding; CTI: Other: Chair of Independent Data Monitoring Committee; National Institute for Health and Care Excellence (NICE): Other: Chair of Technology Appraisal Committee. Osborne:Servier: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; MSD: Honoraria; Roche: Honoraria; Novartis: Honoraria. Bell-Gorrod:Bristol-Myers Squibb: Consultancy; Merck EDM Serono: Consultancy; PharmaMar: Consultancy; Novartis: Consultancy; GlaxoSmithKline: Consultancy. Latimer:Pfizer: Consultancy; BMS: Consultancy; Merck: Consultancy; Astra Zeneca: Consultancy; Bluebirdbio: Consultancy; Janssen: Consultancy. Apperley:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Pocock:Kent & Canterbury Hospital: Employment. Copland:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Clark:Ariad/Incyte: Consultancy; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Abstract 1835: PPARγ agonist in combination with bcr/abl tyrosine kinase inhibitors in patients of chronic myeloid leukemia in chronic phase with suboptimal molecular response

Abstract Introduction &amp; background: Ten to 20 % of patients of Chronic Myeloid Leukemia in chronic phase (CML CP) have suboptimal molecular response (MR) to first line Imatinib maleate (IM). Treatment options include IM dose increase or switch to a 2nd generation tyrosine kinase inhibitor (TKI), Nilotinib or Dasatinib. Recently, synergy has been demonstrated when PPAR γ agonists are added to TKIs. We describe our initial results on 15 patients of CML CP treated with the combination of IM and pioglitazone, a PPAR γ agonist. Patients and methods: Fifteen patients of CML CP with suboptimal MR (bcr/abl:abl RQ-PCR between 1 to 10) after more than two years of IM were recruited in this pilot study. Because of economic considerations, these patients were not candidates for 2nd gen. TKIs. Patients given IM 600 mg/day and pioglitazone 30 mg/day. Blood counts and biochemistry monitored monthly, bcr/abl tested every 3 months using a cartridge based IS assay using the Cepheid GenXpert. Results &amp; conclusions: Twelve of the 15 patients achieved significant MR, with 6/16 achieving a major MR at 9 months. Only 3/15 did not show a response (Table). Treatment with pioglitazone was well tolerated. One patient was not analysed due to intolerance to pioglitazone are first dose. Two patients had grade 1 elevation of hepatic enzymes which returned to normal after one week treatment cessation. We conclude that the combination of imatinib with pioglitazone is effective and well tolerated in patients with a sub-optimal MR to TKI in patients with CML-CP. The combination could be a cost-effective strategy in treating imatinib non/sub-optimal responders in the developing world. The combination needs further and larger studies for confirmation and evaluation of the mechanisms of the synergy. S. No.Patient ID/SexDiagnosis dateBCR-ABL (Before Pio)BCR-ABL (After Pio)At 3 monthAt 6 monthAt 9 month1SCM/MOct 20125.352.741.830.0052MD/FAug 20061.130.880.480.13GPJ/MJan 20142.860.43ND0.54RRC/MOct 20082.861.070.25ND5RK/MMar20081.390.770.350.416RDS/FOct 200010.15.994.870.677RDR/FApril 20039.045.780.360.058MM/MMay 20114.48NDND0.149RD/FJuly 20108.331.290.440.7310RB/FJuly 20153.253.022.891.3911BRR/MJan 20107.135.613.821.7712BK/FNov 20042.060.040.030.0713DPS/MJan 20116.155.471.020.8414JKM/MApril 20074.2215.49.117.6215CS/MOct 20121.721.170.840.08 Citation Format: Hemant Malhotra, Ajay Yadav, Ashwin Mathur, Debashish Biswas, Bharti Malhotra. PPARγ agonist in combination with bcr/abl tyrosine kinase inhibitors in patients of chronic myeloid leukemia in chronic phase with suboptimal molecular response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1835.

Comparative analyses of nilotinib versus high-dose imatinib versus sustained standard-dose imatinib in patients with chronic phase chronic myeloid leukemia following suboptimal molecular response to first-line imatinib

The aim of this study was to investigate the efficacy of nilotinib (NIL) versus high-dose imatinib (IM) versus sustained standard-dose IM for patients with chronic myeloid leukemia (CML) with suboptimal molecular response to first-line IM therapy. Patients with CML who achieved complete cytogenetic response (CCyR) but not major molecular response (MMR) after 18–24 months on first-line IM therapy were enrolled and divided into three treatment cohorts: NIL 800 mg/day (Cohort 1, n = 28) and IM 800 mg/day (Cohort 2, n = 28) in the RE-NICE study, and sustained IM 400 mg/day (Cohort 3, n = 52) in clinical practice. The primary efficacy variable of cumulative rate of MMR by 12 months was not different among the three cohorts. However, the cumulative incidence of MMR by 36 months was significantly higher in Cohort 1 than Cohort 3 (83.1% vs. 57.1%, P = 0.021), but there were no significant differences in Cohort 1 vs. 2 (P = 0.195) and Cohort 2 vs. 3 (P = 0.297). Different profile for adverse events was observed between NIL and high-dose IM therapy. In conclusion, our data suggested that switching to NIL may provide more effective long-term response than sustaining standard-dose IM for patients with suboptimal molecular response to first-line IM.

Efficacy of Nilotinib versus Imatinib in Philadelphia Positive Patients with Chronic Myeloid Leukemia in Early Chronic Phase Who Have a Warning Molecular Response to Imatinib

Background and Objectives: Chronic myeloid leukemia (CML) accounts for approximately 15% of newly diagnosed cases of leukemia in adults. In this study, the efficacy of nilotinib at 400 mg BID is compared with imatinib at 400 mg BID in CML patients with suboptimal molecular response after at least 12 months of daily dose 400 mg of imatinib therapy. Patients and Methods: This study included a total number of 50 patients, divided into two groups (25 patients each). The first group (Group I): Patients received imatinib at 400 mg BID, second group (Group II): Patients had a suboptimal molecular response to imatinib and received nilotinib at 400 mg BID in early chronic phase. During the two years period of data collection, the primary end included median survival. The secondary end included response rate, type of response, duration of response and progression free survival. Also side effects were recorded. Patients were followed up every month by complete and differential blood counts, liver function test, renal function test and (PCR) every three months for two year. Results: Nilotinib group had significantly higher frequency of major molecular response (MMR) where 23 (92%) patients achieved it while only 16 (64%) patients in Imatinib group achieved MMR (P = 0.01). Nilotinib had better toxicities profile than Imatinib. Conclusion: Both Nilotinib and high dose Imatinib achieved response in CML patients with suboptimal response with rapid and deeper molecular response, better survival outcomes and less side effects in nilotinib.

358P PPAR GAMMA Agonist in combination with BCR/ABL TKI in patients of CML-CP with suboptimal molecular response

358P PPAR GAMMA Agonist in combination with BCR/ABL TKI in patients of CML-CP with suboptimal molecular response

358P PPAR GAMMA Agonist in combination with BCR/ABL TKI in patients of CML-CP with suboptimal molecular response

358P PPAR GAMMA Agonist in combination with BCR/ABL TKI in patients of CML-CP with suboptimal molecular response

Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib.

The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy (N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy

Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after ≥18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%–66.3%) and 66.7% (95% CI, 51.0%–80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874.

A Nationwide Observational Study of the Israeli Experience with Ponatinib Outside Clinical Trials in Chronic Myeloid Leukemia

Ponatinib is an oral tyrosine kinase inhibitor (TKI) that has been designed to be effective also in patients who harbor the TKI-refractory threonine to isoleucine mutation at position 315 (T315I). In December 2014 the drug was granted an accelerated approval by the FDA, based on the promising results from the phase II PACE (Ponatinib Ph ALL and CML evaluation) trial. In this trial, 56% of previously treated patients who had resistance to or unacceptable side effects from dasatinib or nilotinib achieved a major cytogenetic response, including 70% of patients with the T315I mutation. Albeit the PACE trial convincingly demonstrated the efficacy of ponatinib, the wide use of the drug has been limited due to safety matters and in particular arterial thrombotic complications, reported in up to 17% of patients. Currently, there is very little real-life information regarding the use of ponatinib outside of clinical trials. The purpose of this study is to characterize patients with chronic myeloid leukemia (CML) who received ponatinib and to assess the effectiveness and safety profile of ponatinib outside of clinical trials.Between 4.2011 and 7.2015 (51 months) 24 patients with CML received ponatinib in 7 medical centers in Israel. We reviewed the medical records of these patients and asked their physicians to rank the quality of life of their patients on a 1 to 5 scale.Prior to ponatinib therapy, patients were treated for a median of 55 months (range: 1 to 215) with 1 to 3 different TKIs (median: 3). In addition 13 patients received at least one course of chemotherapy or interferon and 2 underwent allogeneic bone marrow transplantation.Screening for mutations at the DNA binding domain was performed at least once during the pre-ponatinib follow-up time in most patients (67%, N=16). Mutations were detected in 11 patients (69%) and the T315I mutation was detected in 8 of those.The median age when starting ponatinib was 44 years (rang: 23 to 79). Most patients had advanced disease and their disease was classified as either accelerated (21%, N=5) or blast crisis (41%, N=10) when they started ponatinib. Based on the medical history, 48% were at-risk to develop vascular complications either because of prior cerebrovascular event or myocardial infarction (18%) or because of vascular risk factors (30%). Baseline ECG and cardiac ECHO studies were available in 11 patients. Only two had signs of prior MI in ECG and none had significant structural or functional pathology.At time of analysis the median duration of follow up was 6 months (range <1 to 34 months), 4 patients died and 14 were still receiving ponatinib. Patients discontinued the treatment either because of major cardiovascular events (N=3), severe pancytopenia (N=1), planned bone-marrow transplantation (N=1) or because they were lost to follow-up (N=1). Seventeen patients were available for response assessment at time of analysis and the overall response rate was 77% (N=13). Five of six patients at chronic phase achieved either complete or major molecular response. Eight patients at accelerated phase or at blast crisis (8/11, 72%) achieved either hematological (5/11, 45%) or molecular response (3/11, 27%). Two of those, with hematological response, underwent allogeneic bone marrow transplantation. The median subjective scoring of ponatinib contribution to the quality of life of patients was 2.4 (range 1 to 5). Physicians that gave low scoring mentioned severe weakness, myalgia and cytopenias as a major concern.Conclusions: In real- life setting ponatinib is generally used as a last resort. In our cohort, it was almost exclusively given to patients who experienced failure to previous TKIs. The only exceptions were 2 patients who received ponatinib for suboptimal molecular response and achieved MMR when switched to ponatinib. Only one third of patients tolerated the recommended dose of 45mg. Yet, response rate was still relatively high, suggesting that a daily dose of 30mg might be appropriate.With only 6 months of follow-up we documented 3 cardiovascular events (12%) that prompted discontinuation of the drug and only one patient had a significant prior vascular risk.The high response rate and overall contribution to quality of life in patients with very few alternatives, who already experienced failure of other TKIs, support the use of this treatment for patients with advanced disease. DisclosuresRaanani:Novartis: Other: Advisory Board, Research Funding; BMS: Other: Advisory Board; Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board. Lavie:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Rozovski:Novartis: Other: Advisory board.

Complete Molecular Response due to nilotinib as III line treatment in a patient with CML and F317L point mutation of the Bcr-Abl kinase domain

In 1997, a forty-three years old woman was diagnosed with CML and treated with alfa-Interferon, achieving complete haematological response (CHR). Three years later, patient was switched to hydroxiurea due to thyroid toxicity. For logistic reasons, therapy with imatinib 400 mg/die was initiated only in 2003, obtaining complete cytogenetic response (CCyR) and suboptimal molecular response in twelve months. CCyR and CHR were then lost three years later. Doubling imatinib dose to 800 mg/die gave no positive results. Mutational analysis performed in September 2007 showed F317L point mutation of the Bcr-Abl kinase domain. In October 2007 dasatinib was started and in April 2008 CCyR was reached with suboptimal molecular response. In March 2009 Bcr-Abl transcript progressively increased, and in August 2009 cytogenetic analysis showed loss of CCyR. Therapy with nilotinib 800 mg/die was started, and in October 2009 the patient obtained complete molecular response (CMR). Bcr-Abl kinase-domain point mutations, acquired during first line therapy, are a common cause of resistance to tyrosine kinase inhibitors. While several Bcr-Abl mutations have been identified, involvement of codon 317 has been reported in the literature following treatment with imatinib and dasatinib.

Nilotinib efficacy in a patient resistant to imatinib

Imatinib, a BCR-ABL inhibitor, is the standard of care for the first-line treatment of patients with chronic-phase CML. Despite the optimal results, some patients develop resistance to imatinib. For these patients, the second-generation tyrosine kinase inhibitors represent effective therapeutic options. Here, we describe a report about a young patient with CML developing resistance to imatinib due to BCR-ABL kinase domain mutations. After six months of treatment with imatinib 400 mg daily, the patient had complete cytogenic response, while at 12 months he had a sub-optimal molecular response, that is a “warning” according to the European LeukemiaNet guidelines (both 2006 and 2009). At 29 months, persisting the sub-optimal molecular response, we decided to increase the imatinib dose up to 800 mg daily. Even after the dose escalation, the patient couldn’t achieve a major molecular response. Therefore we subjected him to a mutation screening, that highlighted L248V mutation. After switching to nilotinib the patient has resulted in complete cytogenic response and major molecular response.

Final Results From SENSOR: Switch to Nilotinib After Molecular Suboptimal Response (SoR) to Frontline Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Abstract Background: Nilotinib elicits faster, deeper molecular responses than imatinib as frontline treatment for CML-CP and is also approved as second-line treatment for patients (pts) intolerant of or resistant to imatinib.However, the optimal management of pts with SoR to frontline imatinib treatment has not been determined. Here, we present final data from the Study to Evaluate Nilotinib in CML pts with SubOptimal Response (SENSOR, NCT0104387), in which adult pts with molecular SoR to frontline imatinib switched to nilotinib. Methods: In this multicenter, open-label study, 45 pts received nilotinib 400 mg twice daily with 24 mo of follow-up. All pts had SoR per 2009 European LeukemiaNet criteria—complete cytogenetic response (CCyR) but no major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) after ≥ 18 mo of frontline imatinib. The primary endpoint was rate of MMR at 12 mo after switch to nilotinib. BCR-ABL1IS transcript levels using ABL1as a control gene were centrally evaluated monthly (mo 1-3), then every 3 mo. Durable MMR at 24 mo was defined as MMR at both 12 and 24 mo with no intermediate loss of MMR. MR4 and MR4.5 were defined as BCR-ABL1IS ≤ 0.01% and ≤ 0.0032%, respectively. Mutation analyses by direct sequencing were performed at baseline (BL) and at end of study for all pts. Retrospective mutational analyses were performed even in pts who did not have any mutations identified at BL or at the end of study visit. Results: Pts were enrolled from Dec 2009 to Feb 2012; 39 pts completed the study and 6 discontinued. Reasons for discontinuation were adverse events (AEs; n = 3), disease progression (n = 1), and withdrawn consent (n = 2). Median dose intensity of nilotinib was 748.9 mg /day (range, 183-799 mg) for a median duration of exposure of 22.1 mo (range, 0.1-22.7 mo). The primary endpoint was met; the rate of MMR at 12 mo was 51.1% (the expected value was 40%). Median time to first MMR among pts who achieved MMR (N = 23) was 2.28 mo, and 51.1% of pts had durable MMR. The proportion of pts achieving MMR as well as deeper molecular responses (MR4, MR4.5) increased over time (Figure). Rates of MMR, MR4, and MR4.5 were 66.7%, 11.1%, and 6.7%, respectively, at 24 mo. By 24 mo, the cumulative rates of MMR, MR4, and MR4.5 were 75.6%, 13.3%, and 6.7%, respectively. Overall, BCR-ABL1 levels decreased during treatment. The median BCR-ABL1IS ratio was 0.24% (range, 0.1%-3.5%) at BL (n = 45) and 0.06% (range, ≤ 0.0032%-2.3%) at 24 mo (n = 40). The slope of BCR-ABL decline was steepest in the first 3 mo after switch to nilotinib. Univariate and multivariate analyses of factors associated with molecular responses at 24 mo will also be presented. Among 30 pts with MMR at 24 mo, 4 pts (13.3%) had BCR-ABL1 mutations at BL, and 17 pts (56.7%) had newly detected (post-BL) mutations (Table). One pt with a newly detected T315I mutation never achieved MMR, progressed to blast crisis after 5.4 mo, and died at 9.4 mo. No other pt progressed or died. The most common any-grade AEs were hyperbilirubinemia (53.3%), nasopharyngitis (46.7%), and headache (37.8%). Elevated lipase level (20.0%) and hypophosphatemia (15.6%) were the most common grade 3/4 AEs. Conclusions: Switching from imatinib to nilotinib resulted in 66.7% of pts achieving MMR at 24 mo and a cumulative incidence of MMR of 75.6% by 24 mo. Some pts achieved even deeper molecular responses. These responses were achieved regardless of BL mutation status and new mutations/splicing abnormalities detected on treatment, except for T315I. Further study is required to determine the impact of the mutations on the efficacy of nilotinib. The safety profile of nilotinib was consistent with prior studies. Figure. Molecular Responses Over Time Figure. Molecular Responses Over Time Table. MMR at 24 mo by BCR-ABL1 Mutation Status (Assay Method: Direct Sequencing) With MMRn = 30 Without MMRn = 15 BLn (%) Post-BLn (%) BLn (%) Post-BLn (%) No mutation 26 (86.7) 13 (43.3) 15 (100) 6 (40.0) Any mutation 4 (13.3) 17 (56.7) 0 9 (60.0) Insensitive T315I 0 0 0 1 E255K 1 0 0 0 Others (occurring in &gt; 2 pts) Exon 8/9 35 base pair insertion 1 9 0 9 Exon 7 deletion 1 4 0 3 Disclosures Yamamoto: Novartis Pharma K.K.: Honoraria, Research Funding; Pfizer Inc.: Research Funding, Speakers Bureau, support with manuscript preparation, support with manuscript preparation Other; ARIAD Pharmaceuticals, Inc: Research Funding. Taniwaki:Novartis: Honoraria, Research Funding. Kimura:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Ohyashiki:Novartis Pharma K.K.: Honoraria, Research Funding, Speakers Bureau. Kawaguchi:Novartis Pharma: Honoraria. Matsumura:Novartis Pharma KK: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria. Hino:Novartis Pharma: Research Funding. Kondo:Novartis Pharma K.K.: Employment. Aoki:Novartis Pharma K.K.: Employment. Okada:Novartis: Employment. Yanada:Novartis: Consultancy.

Efficacy of Nilotinib Vs High-Dose Imatinib Vs Sustaining Standard-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Response to Frontline Imatinib

Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of nilotinib (NIL) versus high-dose IM versus sustaining standard-dose IM for CCyR patients with suboptimal molecular response to frontline IM therapy.Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were divided into 3 treatment groups; NIL 400mg BID (800 mg/day; group 1) vs IM 400 mg BID (800 mg/day; group 2) vs IM 400mg QD (400mg/day; group 3). Group 1 and 2 patients were selected in RE-NICE multicenter study and group 3 patients were selected with the same inclusion criteria of RE-NICE.The efficacy endpoints are MMR rate by 12 months and MMR rate and undetectable molecular residual disease (UMRD) rates by 36 months. Safety profiles of each group were compared.Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or intolerance to treatment were allowed to switch to other treatment.Results. With a data cut-off date of 17 Jul 2014, a total of 83 patients were evaluated; 29 patients in NIL group (group 1), 29 patients in high-dose IM group (group 2) and 25 patients in standard-dose IM group (group 3).With a median follow-up of 36 months (range, 1-63), all patients in group 1 remained in nilotinib treatment, 17 patients in group 2 switched to NIL 400mg BID due to intolerance (n=4) and lack of response (no MMR; n=13). In group 3, with a median follow-up of 71 months (range, 6-132), 15 patients switched to other treatment due to intolerance (n=5) and lack of response (no MMR; n=10).Up to now, all patients in three groups have maintained CCyR without progression or resistance.10 in 29 (35%), 8 in 29 (28%) and 5 in 25 (20%) patients achieved MMR by 12 months, and 20 in 29 (69%), 15 in 29 (51%) and 11 in 25 (44%) patients achieved MMR by 36 months in group 1, group 2 and group 3 respectively. Overall, 3 patients in group 1 (3/29, 10%) achieved confirmed UMRD.Overall 3 years probability of MMR was significantly higher in group 1 than the other two groups (67.8% vs 41.0% vs 40.4%, group 1, 2, 3 respectively, group 1 vs 2, P=0.089, group 1 vs 3, P=0.035, group 2 vs 3, P=0.614).Compare to other groups, the patients in group 2 showed higher toxicities, such as leukopenia, anemia, thrombocytopenia, edema, fatigue, dyspnea and hypophosphatemia.Conclusions. Nilotinib 400mg twice daily treatment showed better efficacy than high-dose or same standard-dose imatinib for the treatment of patients who have suboptimal molecular response to initial standard-dose imatinib. Additionally, a switch to nilotinib in suboptimal molecular responder to imatinib would also be preferable option in terms of tolerability. Updated data with longer follow-up duration will be presented in the meeting. DisclosuresNo relevant conflicts of interest to declare.

Nilotinib Or High-Dose Imatinib Compared With Standard-Dose Imatinib In Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses To Standard-Dose Imatinib: Including Updated Data From RE-Nice Study

BackgroundIn chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of switching to nilotinib (NIL) versus high-dose IM versus standard-dose IM for patients with suboptimal molecular response to IM as first-line therapy. MethodsEarly chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in RE-NICE study, and informed consents were obtained from all patients. In NIL arm, patients received 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. The efficacy of switching to NIL or high-dose IM were compared with that of the patients who maintained standard-dose of IM. Patients with standard-dose IM were selected with the same inclusion criteria and maintained standard-dose IM after enrollment period. To compare the efficacy among three groups, MMR rate, MR4.0 and undetectable molecular residual disease (UMRD) rates by 12 months were analyzed. Safety profiles also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. ResultsWith a data cut-off date of 15 Jul 2013, a total of 52 patients were randomized into NIL arm (n = 26) or high-dose IM arm (n = 26) and 16 patients were included in standard-dose IM group. With a median follow-up of 21 months (range, 1-36) in NIL arm and high-dose IM arm, all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. With a median follow-up of 12 months (range, 1-60), all patients in standard-dose IM group have maintained CCyR without progression to advanced disease. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (41.1% vs 28.8, P = 0.334). Only in NIL arm, 2 in 26 (8%) achieved confirmed MR4.0 and UMRD. By 12 months, 10 in 26 (39%), 7 in 26 (27%) and 3 in 16 (19%) patients achieved MMR, in NIL arm, high-dose IM arm and standard-dose IM group respectively. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as leucopenia, anemia, Thrombocytopenia, edema, fatigue, dyspnea and decreased phosphate. In addition, 14 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=11) and intolerance (n=3), and the median duration of NIL treatment was 23 months (range, 2-36 months). Among them, 6 (43%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 0-18). ConclusionsThese results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures:No relevant conflicts of interest to declare.

Nilotinib Following Molecular Suboptimal Response (SoR) To Imatinib In Japanese Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP): 12 Month Follow-Up From The SENSOR Study

BackgroundNilotinib has shown superiority over imatinib for treating pts with newly diagnosed CML-CP. Additionally, pts who are resistant or intolerant to imatinib can often achieve improved responses by switching to nilotinib. However, the value of switching pts to nilotinib due to molecular SoR on imatinib is not well characterized. The Study to Evaluate Nilotinib in CML pts with SubOptimal Response (SENSOR) was therefore conducted to evaluate the efficacy and safety of nilotinib 400 mg BID in pts with CML-CP with SoR to frontline imatinib. Here, we present results of a planned 12-mo interim analysis. MethodsSENSOR (NCT01043874) is an open-label, multicenter, phase IV study. Adult pts with CML-CP in complete cytogenetic response but not in major molecular response (MMR; defined as BCR-ABL ≤ 0.1% on the International Scale [IS]) after ≥ 18 mo on frontline imatinib (SoR as defined by 2009 European LeukemiaNet criteria) were eligible to enroll and switch to nilotinib 400 mg BID. Molecular responses were assessed prior to enrollment, at 1, 2, and 3 mo and every 3 mo thereafter. Mutational analyses were performed at baseline (BL) and at end of study in all pts, every 3 mo in pts with BL mutations, and with any ≥ 5-fold increase in BCR-ABL from the lowest level in pts not in MMR. All of these assays were done at a single central laboratory. The primary endpoint was the rate of MMR at 12 mo. Planned enrollment was 45 pts in order to provide a ≥ 25% lower limit of the 95% CI with an expected MMR rate of 40%. Planned follow-up was 24 mo. ResultsPlanned enrollment of 45 pts was completed between Dec 2009 and Feb 2012. Median age of pts was 47 years (range, 19-80). Pts had received imatinib for a median of 23.0 mo (range, 17.0-103.3) at a median daily dose of 400 mg (range, 297-628). Median BL BCR-ABL/ABL ratio was 0.24% (range, 0.11-3.49). At the cutoff date, 19 pts (42%) had completed the study (24 mo follow-up), and 21 (47%) had nilotinib treatment ongoing. Median nilotinib duration was 19.1 mo (range, 0.1-22.7) and median dose intensity was 733 mg/day (range, 183-800). Five (11%) pts discontinued from study treatment for the following reasons: adverse events (AEs; n = 2), disease progression (n = 1), withdrawal of consent (n = 1), and administrative problems (n = 1).At 12 mo, the MMR rate was 51.1% and the median BCR-ABL/ABL ratio was 0.10% (range, ≤ 0.0032-1.62). The cumulative rate of MMR by 12 mo was 66.7%. Among 34 pts with MMR at any time, median time to first MMR was 2.28 mo. No pt who achieved MMR had confirmed loss of MMR (BCR-ABLIS > 0.1% with a ≥ 5-fold increase in BCR-ABL transcripts from the lowest level achieved on study in 2 consecutive samples) by the cutoff date (Table). Two pts (4.4%) achieved BCR-ABLIS ≤ 0.0032% at 12 mo.BCR-ABL mutations were detected at BL in 5 pts (E255K, E459K + exon 8/9 35 base pair insertion, Q252R, M244V, and exon 7 deletion), all of whom achieved MMR on nilotinib. Mutations were identified during treatment in 13 pts, 2 of whom had the same mutation at BL; 10 of these pts achieved MMR. One pt developed a T315I mutation, progressed at 5.4 mo, and died at 9.4 mo. These were the only reported events for progression-free survival and overall survival (1 each).The safety profile of nilotinib was consistent with previous studies. Drug-related AEs (any grade) occurring in ≥ 20% of pts included hyperbilirubinemia (53.3%), increased ALT (28.9%), headache (28.9%), hypophosphatemia (26.7%), rash (26.7%), and increased lipase (24.4%). Grade 3/4 newly occurring/worsening abnormal hematology values were hemoglobin (6.7%), neutrophils (4.4%), platelet count (2.2%), and decreased total white blood cells (2.2%). Six pts had serious AEs (2 with suspected relation to study drug [anemia and erythema multiforme]). ConclusionsAfter switching to nilotinib, MMR was rapidly achieved in the majority of pts. These results support the clinical benefit of switching to nilotinib in pts with molecular SoR to imatinib. Disclosures:Miyamura:Novartis: Speakers Bureau; JRC Nagoya 1st Hospital: Employment. Miyamoto:Kyushu University Hospital: Employment. Kurokawa:Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Yamamoto:Novartis: Honoraria, Research Funding. Taniwaki:Novartis: Honoraria. Kimura:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Ohyashiki:Novartis: Honoraria, Research Funding. Kawaguchi:Novartis: Honoraria. Matsumura:Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Tsurumi:Novartis: Honoraria. Hino:Novartis: Research Funding. Tadokoro:Novartis: Guest speaker in a scientific meeting sponsored by Novartis Other. Hyodo:Hiroshima University: Employment. Kubo:Aomori Prefectural Central Hospital: Employment; Novartis: Honoraria. Kondo:Novartis: Employment. Amagasaki:Novartis: Employment. Kawahara:Novartis: Employment. Yanada:Novartis: Consultancy.

Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study

AbstractAbstract 3775 Background.In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods.Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results.With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions.These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Efficacy of Nilotinib in EARLY Chronic PHASE CML Patients WHO Have Suboptimal Cytogenetic or Molecular Response to Imatinib. A Multicentric Retrospective Study

AbstractAbstract 4454The CML-CP suboptimal responders rappresent an eterogenous group of patients in which it is possible either to obtain an optimal renponse or to experiment a failure. The Clinical data of MDACC, Hammersmith Hospital and GIMEMA group showed that patients with suboptimal response at 6 and 12 months have worse long term outcomes than patients with optimal responses, particularly if the suboptimal response occurs early in the treatment, suggesting an advantage for pts with early major molecular response, expecially for event free survival and progression free survival. Moreover, recently, the German group has shown the benefit of early major molecular response on overall survival too. So earlier use of nilotinib or dasatinib in suboptimal CP CML may be beneficial in two potential ways:by promoting an early response, thereby potentially improving prognosis; by avoiding the development of treatment resistance.The clinical challenge in this setting would be to accurately identify patients who are likely to fail treatment with TKIs.This retrospective analysis was designed to explore the efficacy of the early switch to Nilotinib in patients with suboptimal responses to imatinib (IM) according to ELN raccomandations.In this multicentric retrospective study, 15 CML-CP patients with suboptimal response to IM within 24 months from diagnosis were evaluated: 4pts with a low, 3 with intermedied and 5 with high Sokal score. The best response to IM was CCyR for 6 pts, PCyR for one pt and Complete Hematological Response for 5 pts. As for suboptimal responses, 5 pts were defined in suboptimal cytogenetic response: 2 pts at 12 months and 2 pts at 6 months; 6pts were 18 months suboptimal molecular responders and 1 pt had a loss of CCyR at 12 months.All patients were switched to Nilotinib 400 mg twice daily. Bone marrow was done at baseline in all pts and at 3,6,12 and 18 months in cytogenetic suboptimal pts, while the molecular analysis was performed on peripheral blood every three months in all other pts.12 pts have been treated with Nilotinib for a median of 17,5 months (range 3–37), 9 patients for ≥ 12 months. Before switching to Nilotinib, pts were treated with IM 400 mg once daily apart for 2 patients who needed an adjustment dose to 300 mg and 600 mg for toxicity and suboptimal response, respectively.Among 6 pts with suboptimal CyR, 4 obtained CCyR, 3 at 3 months and one at 6 months; 2 pts had any response at the milestones timepoints and they switched to another therapy. All pts with molecular suboptimal response obtained MMR at 3 months apart for one, who showed MMR at 12 months.Nilotinib was well tolerated in all 12 pts; only one developed a moderate transaminase elevation. A brief drug intrerruption was sufficient to manage this adverse event.Our data confirm that second generation TKIs give deeper and earlier responses also in second line treatment, garantendo optimal PFS and OS. In our serie infact, Nilotinib treatment results in high and relatively quick cytogenetic and molecular response rate in CML –CP-pts with suboptimal response to IM.These results demonstrate that the early switch to Nilotinib could be raccomanded in suboptimal responders in order to improve the outcome of this kind of pts and strongly suggest the second generation TKI as first line therapy in CML patients. A larger patient population and a longer period of observation could allow to confirm these preliminary data. Disclosures:No relevant conflicts of interest to declare.

Suboptimal response in chronic myeloid leukemia patients treated with imatinib: Early identification and new therapeutic challenges

In 2006 European LeukemiaNet proposed recommendations to define several categories of chronic myeloid leukemia patients treated front-line with imatinib. In 2009 an update of these recommendations was published: whereas it is clear how important is to switch rapidly to a second line of treatment in failure patients, the correct treatment of patients with sub-optimal response is still a matter of debate. Several groups have indeed shown that prognosis of patients with sub-optimal cytogenetic response is similar to that of failure patients, whereas lack of data exists for patients with sub-optimal molecular response at 18months. In this article, we overview studies demonstrating prognostic implications of being suboptimal responders to imatinib as well as results of recent clinical trials testing new generation tyrosine kinase inhibitors in this setting.