Advanced CML Research Articles

BCR/ABL-Positive Chronic Myeloid Leukemia in Children: Current Treatment Approach.

The purpose of this review is to summarize the most updated treatment recommendations for pediatric CML, and to discuss current areas of investigation. There is new phase 1 data to support the safety of the non-ATP competitive tyrosine kinase inhibitor (TKI) asciminib in the pediatric cohort. Ongoing studies are investigating the role of treatment-free remission in children. Chronic phase CML in children is managed with lifelong TKI therapy; however, evidence of deeper remissions sustained with second-generation TKIs may permit shorter treatment courses. Use of more specific TKIs may mitigate some of the side effects specific to the pediatric cohort. Children with advanced phase CML should achieve a complete hematologic remission with use of a second-generation TKI prior to transplant to achieve the best outcome.

Erythroid variant evolving from chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitors: a rare case report

BackgroundChronic myeloid leukemia (CML) is characterized by the presence of BCR::ABL1 fusion gene resulting from a reciprocal translocation, t(9;22)(q34;q11.2), leading to prominent granulocytic proliferation. The majority of patients initially present in chronic phase (CP), which may progress to advanced CML with predominantly granulocytic phenotypes in the absence of proper treatment or response to tyrosine kinase inhibitors (TKIs). We present an exceptionally rare case in which an erythroid variant emerged from a CML patient resistant to multiple TKIs. This variant is characterized by the detection of t(9;22) BCR::ABL1 fusion in erythroid precursors at various maturation stages and the absence of granulocytic progenitor hyperplasia typically seen in classical CML.Case presentationA 33-year-old female with CP-CML had received multiple TKI therapies since her initial diagnosis in 2015. Due to intolerable side effects and inconsistent adherence, she exhibited an inadequate response and developed new-onset pancytopenia. Bone marrow (BM) biopsy specimen revealed a hypercellular marrow with significant erythroid hyperplasia (90% of marrow cellularity) and a reversed myeloid-to-erythroid (M: E) ratio of 1:10. Both erythroid and myeloid cells displayed progressive maturation without dysplasia or excess blasts. Chromosomal analysis identified t(9;22) (q34;q11.2) in 19 out of 20 metaphase cells. BCR::ABL1 fusion transcript (p210 isoform) was confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) and next-generation sequencing (NGS). Notably, no additional pathogenic cytogenetic abnormalities or ABL1 kinase domain mutations were detected. Here, we report the first published case of an erythroid variant emerging in a CML patient resistant to multiple TKIs—a distinct entity from the erythroid blast crisis evolving from CML.ConclusionThe erythroid variant of CML is distinguished by the presence of t(9;22) (q34;q11.2) BCR::ABL1 in predominant erythroid precursors at different stages of maturation. In a myeloid neoplasm showing predominant erythroid hyperplasia without typical CML features, it is vital to correlate morphology and t(9;22) BCR::ABL1 cytogenetic testing for accurate diagnosis, and to prevent confusion with PEL transformation in CML.

Chromosomal Instability in Chronic Myeloid Leukemia: Mechanistic Insights and Effects.

Simple SummaryChronic myeloid leukemia is a disease diagnosed by the presence of the Philadelphia chromosome, which leads to the BCR::ABL fusion oncoprotein and overactive tyrosine kinase activity. Multiple other genetic aberrations and chromosomal changes make the disease very heterogeneous, and these changes increase as the disease becomes more aggressive. Understanding the cause and effects of chromosomal instability in CML might help to improve treatment options and monitoring of patients with advanced phases of CML.The most recent two decades have seen tremendous progress in the understanding and treatment of chronic myeloid leukemia, a disease defined by the characteristic Philadelphia chromosome and the ensuing BCR::ABL fusion protein. However, the biology of the disease extends beyond the Philadelphia chromosome into a nebulous arena of chromosomal and genetic instability, which makes it a genetically heterogeneous disease. The BCR::ABL oncoprotein creates a fertile backdrop for oxidative damage to the DNA, along with impairment of genetic surveillance and the favoring of imprecise error-prone DNA repair pathways. These factors lead to growing chromosomal instability, manifested as additional chromosomal abnormalities along with other genetic aberrations. This worsens with disease progression to accelerated and blast phase, and modulates responses to tyrosine kinase inhibitors. Treatment options that target the genetic aberrations that mitigate chromosome instability might be a potential area for research in patients with advanced phase CML.

An evaluation of ponatinib as a therapy in adult patients with resistant/intolerant chronic-phase chronic myeloid leukemia

Introduction: Chronic myeloid leukemia is now a highly treatable leukemia due to the availability of multiple tyrosine kinase inhibitors (TKIs) inhibiting the BCR-ABL1 oncogene. Some patients with CML can display resistance or intolerance to multiple TKIs, oftentimes due to the presence of mutations in BCR-ABL1, such as T315I, which limits effective treatment options. Ponatinib is a third-generation, rationally-designed TKI with clinically meaningful activity in this difficult-to-treat population. Ponatinib is associated with an increased risk of arterial occlusive events (AOEs) which has required a re-examination of its dosing in order to limit the risk of these events. Areas covered: This review will provide an overview of the mechanism of action of ponatinib and the safety and efficacy data from clinical trials in chronic myeloid leukemia Expert opinion: Ponatinib is a potent pan-BCR-ABL1 TKI with substantial activity in patients with more resistant or advanced CML. Its efficacy needs to be balanced with the increased risk of vascular events, which seems to be at least partially diminished by the implementation of mitigation strategies aimed at modifying cardiovascular risk factors and adaptive dosing of the drug.

Aberrant hydroxymethylation in promoter CpG regions of genes related to the cell cycle and apoptosis characterizes advanced chronic myeloid leukemia disease, poor imatinib respondents and poor survival

BackgroundThere is strong evidence that disease progression, drug response and overall clinical outcomes of CML disease are not only decided by BCR/ABL1 oncoprotein but depend on accumulation of additional genetic and epigenetic aberrations. DNA hydroxymethylation is implicated in the development of variety of diseases. DNA hydroxymethylation in gene promoters plays important roles in disease progression, drug response and clinical outcome of various diseases. Therefore in this study, we aimed to explore the role of aberrant hydroxymethylation in promoter regions of different tumor suppressor genes in relation to CML disease progression, response to imatinib therapy and clinical outcome.MethodsWe recruited 150 CML patients at different clinical stages of the disease. Patients were followed up for 48 months and haematological/molecular responses were analysed. Haematological response was analysed by peripheral blood smear. BCR/ABL1 specific TaqMan probe based qRT-PCR was used for assessing the molecular response of CML patients on imatinib therapy. Promoter hydroxymethylation of the genes was characterized using MS-PCR.ResultsWe observed that promoter hydroxymethylation of DAPK1, RIZ1, P16INK4A, RASSF1A and p14ARFARF genes characterize advanced CML disease and poor imatinib respondents. Although, cytokine signalling (SOCS1) gene was hypermethylated in advanced stages of CML and accumulated in patients with poor imatinib response, but the differences were not statistically significant. Moreover, we found hypermethylation of p14ARF, RASSF1 and p16INK4A genes and cytokine signalling gene (SOCS1) significantly associated with poor overall survival of CML patients on imatinib therapy. The results of this study are in agreement of the role of aberrant DNA methylation of different tumor suppressor genes as potential biomarkers of CML disease progression, poor imatinib response and overall clinical outcome.ConclusionIn this study, we report that promoter hydroxymethylation of DAPK1, RIZ1, P16INK4A, RASSF1A and p14ARFARF genes is a characteristic feature of CML disease progressions, defines poor imatinib respondents and poor overall survival of CML patients to imatinib therapy.

Anticancer Activity and Molecular Mechanism of Momordica cochinchinensis Seed Extract in Chronic Myeloid Leukemia Cells

Targeting Bcr-Abl is the key to the treatment of chronic myeloid leukemia. Despite great progress in the treatment of patients with chronic CML, advanced CML patients are still unable to obtain effective and safe drugs. Momordica cochinchinensis seed is the dried ripe seed of Momordica cochinchinensis, which is a kind of fruit and consumed for dietary as well as medicinal uses. This study aimed to investigate the anticancer activity of Momordica cochinchinensis seed extract (MCSE) in CML cells. CML cells (KBM5 and KBM5-T315I) were treated with MCSE and analyzed for growth, apoptosis, and signal transduction. Nude mouse xenograft model was used to evaluate the antitumor activity of MCSE In Vivo. MCSE significantly reduced the cell viability of CML cells, triggered G0/G1 phase arrest in KBM5 cells and S phase arrest in KBM5-T315I cells. Concurrently, MCSE caused the activation of caspase-3, -8, -9, PARP and the degradation of Mcl-1, ultimately triggering endogenous and exogenous cell apoptosis. Meanwhile, MCSE downregulated Bcr-Abl levels and its downstream signaling pathways. Additionally, MCSE inhibited the growth of CML cells in nude mouse xenografts. Taken together, this study demonstrated the anticancer mechanism of MCSE, namely blocking Bcr-Abl and downregulating Mcl-1, and finally induced apoptosis of CML cells.

COVID-19 in Patients with Chronic Myeloid Leukemia: Poor Outcomes for Patients with Comorbidities, Older Age, Advanced Phase Disease, and Those from Low-Income Countries: An Update of the Candid Study

COVID-19 in Patients with Chronic Myeloid Leukemia: Poor Outcomes for Patients with Comorbidities, Older Age, Advanced Phase Disease, and Those from Low-Income Countries: An Update of the Candid Study

Interim Results of a Phase 2 Clinical Trial Using Mb-IL21 Ex Vivo Expanded NK Cells to Enhance Graft Versus Leukemia Effect for Patients with Myeloid Malignancies after Haploidentical Transplantation

▪Background: Disease relapse has emerged as the most common cause of treatment failure after transplantation. Natural killer (NK) cells have potent antitumor and antiviral effects. We hypothesized that multiple infusions of ex vivo expanded NK cells administered in early post-transplant will enhance graft-versus-leukemia (GVL) effect and began a phase 1/2 clinical trial in haploidentical transplant patients (clinicaltrials.gov NCT01904136).Methods: Results from the phase 1 clinical trial were recently reported. The aim was to determine the maximum tolerated dose of ex vivo expanded NK cells with a K562 expressing mb-IL21 feeder cell system in patients with myeloid malignancies (AML/MDs/CML). Patients received conditioning with melphalan 140mg/m2, fludarabine 160mg/m2 and 2GyTBI, and GVHD prophylaxis with post-transplant cyclophosphamide, tacrolimus and mycophenolate. All patients had bone marrow graft. NK cells were generated from peripheral blood mononuclear cells of the same donor and infused fresh on Day -2, and cryopreserved on Day +7 and +28 (up to 90). Having an NK-cell alloreactive donor or certain KIR genotype was not a requirement to participate in this study, although these characteristics were evaluated in all patients. In the phase 1 study dose escalation patients received NK cells starting at 1x105 to 1x108/Kg/dose for 3 doses. No dose limiting toxicities were observed in the phase 1 study. 1x108/kg/dose was chosen for the phase 2 trial.Results: Twenty patients were treated to date, 13 on the phase 1 study and 7 on the phase 2 part. The median age was 45 years (range 18-59), the median follow-up survivors was 16.5 months. Twelve patients (60%) were females. The median HCT-CI was 2 (range 0-8). Ten patients (50%) had AML (9 in CR1 and 1 beyond CR2), 3 (15%) had MDS (2 with induction failure, 1 untreated), and 7 (35%) had advanced CML (4 in CP2 after progression to blast-phase of which 2 in CNS, 1 in CP1, 1 clonal evolution). Of the patients with AML 4 patients with AML had poor-risk cytogenetics and 6 had intermediate with high-risk mutations except one (2 had FLT3, 2 had NRAS, 1 had ASXL1) and 3 patients had primary induction failure. Two MDS patients had complex cytogenetics and one diploid with high percent of bone marrow blasts. DRI was very high/high in 10 patients and intermediate/low in 10 patients. All patients received all 3 NK cell infusions as planned except one patient. Eight patients received the maximum dose of 1x108/kg/dose.One patient had early death due to hemorrhage. Nineteen patients were evaluable for engraftment and all achieve primary engraftment after a median time of 19 days (range 16-42). Nine of 12 female patients (75%) had donor-specific anti-HLA antibodies. Chimerism was 100% donor in all patients except one who had mixed chimerism. The cumulative incidence (CI) of all aGVHD at Day100 and 1 year post-transplant was 26.1% and 48% (3 patients had late acute GVHD), exclusively grade 2 and exclusively GI tract. No grade 3 or grade 4 aGVHD, and no chronic GVHD was observed. Also, none of the patients developed liver GVHD. The CI of TRM at 1 and 2 years post-transplant was 5.6% and 16.7%, respectively. Only one patient relapsed to date for a CI of relapse at 1 and 2 years on 5.6%. The only patient who relapsed was an advanced FLT3+AML patient (beyond CR2) who received the lowest NK cells dose. None of the patients who received ≥1x105/kg dose relapsed. The median overall survival and progression-free survival (PFS) were not reached. The 1-year and 2-years PFS was 84.4% and 74%, respectively (Figure 1). Eight of 19 patients (42%) reactivated CMV and 4 patients (21%) had grade 1 transient BKV cystitis.Conclusions: Multiple infusions of high doses of donor-derived ex vivo expanded NK cells with a K562 feeder cell system and mbIL-21 administered early post-transplant are safe and are associated with low relapse rate and low incidence of viral reactivation. A randomized trial is needed to confirm these results. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding. Lee:Courier Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees; Cyto-Sen Therapeutics, Inc: Other: Founder, Vice President, Medical Director; Intellia Therapeutics, Inc: Consultancy; Miltenyi: Speakers Bureau.

The Outcome of Patients with Advanced Phase Chronic Myeloid Leukemia with and without Allogeneic Hemopoietic Stem Cell Transplantation

Introduction: In spite of the widespread use of second- and third-generation tyrosine kinase inhibitors (TKIs) the prognosis of patients with advanced phase CML (accelerated phase (AP) or blast crisis (BC)) is still dismal. The aim of this study was to compare outcomes in advanced phase CML cohorts based on whether or not these patients received allogeneic hemopoietic stem cell transplantation (allo-HSCT). Patients and methods: A total of 162 patients with AP/BC-CML with (allo-HSCT+TKIs, n=20/62,) or without (n=10/70, TKI) history of allo-HSCT were included in this retrospective study. All patients received allo-HSCT with a reduced-intensity conditioning regimen with fludarabine 180 mg/m2 and busulfan 8-12 mg/kg or melphalan 140 mg/m2. Forty-two patients received TKIs for post-transplant relapse prophylaxis. In the majority of cases dasatinib was used (n=36). In the remaining 80 patients alloHSCT was not performed due to refusal for personal reasons or delay in referral to transplant center. They were included in TKI-group and were treated with chemotherapy+TKIs (60) or TKIs only (20). Eighty-one percent received second or third line TKIs. There were no significant differences in age, sex, comorbidity status, disease phase, and additional chromosomal aberrations incidence between allo-HSCT+TKI and TKI groups (Table 1). Overall survival (OS) was defined as the time from the start of treatment (allo-HSCT/TKI, chemotherapy) to death, event-free survival (EFS) - as the time between commencement of treatment and loss of response or post-transplant relapse, death. Response was defined according to European Leukemia Net and National Comprehensive Cancer Network recommendations. All patients signed an informed consent for processing of personal data; the trial was approved by Pavlov University local ethical committee. Results: The median follow-up was 44 months (1-344). The engraftment was documented in 71 (86%) patients. The cumulative incidence of non-relapse mortality at day 100 and 1 year after allo-HSCT were 10% and 18%, respectively. Grade 2-4 acute graft versus host disease (GVHD) was documented in 21 (29%), grade 3-4 acute GVHD - 14 (20%), chronic GVHD - 18 (27%) including mild, moderate and severe form in 6 (9%), 8 (12%) and 4 (6%) patients, respectively. Two-year cumulative incidence of relapse was 39%. Twenty-four patients received donor lymphocyte infusions and TKIs after relapse, in 4 cases chemotherapy was added. In four cases only TKIs were administered to treat relapse. Nine patients achieved sustained complete molecular response (CMR), in 19 cases disease progression was documented. The data on response was available for 71 patients in TKI group. Among patients with BC 36 (59%) patients did not respond to therapy, while complete hematological response (CHR), complete cytogenetic response (CCR) and CMR were achieved in 22 (34%), 1 (2%) and 2 (3%) cases, respectively. Nine patients (90%) without BC history achieved response to therapy (CHR 5, CCR 2, CMR 2), while 1 patient failed to respond. Sixty-nine patients died; all deaths were CML-related. Four-year OS was 58% in allo-HSCT+TKIs versus 33% in TKI group (p=0.032) (Figure 1A). However, there was no significant difference in 4-year EFS between groups: 35% vs. 17% (p=0.5), accordingly. BC at the moment of allo-HSCT significantly worsened 4-year OS: 23% vs. 63% (p=0.007). The 4-year OS in patients transplanted in BC (n=10) was comparable to one in TKI group: 23% vs. 33% (p=0.3) (figure 1B). Conclusions: Allo-HSCT still has an advantage as potentially curative treatment for part of advanced phase CML patients even in the presence of new generation TKIs. Allo-HSCT in BC is associated with worse outcome. An earlier referral of these patients to the transplant center can improve the outcome of allo-HSCT and prognosis.. Disclosures No relevant conflicts of interest to declare.

Improved Outcomes for Patients Receiving High-Doses of IL-21 Ex Vivo Expanded NK Cells after Haploidentical Transplantation (haploSCT): Long-Term Follow-up of a Phase 1/2 Clinical Trial with Comparison to CIBMTR Controls

Background: Disease relapse following allogeneic stem-cell transplantation remains unacceptably high and there is an urgent need for new therapies that decrease relapse rates and improve survival post-transplant. Natural killer (NK) cells have potent antitumor effects, particularly those expended with mb-IL21 from peripheral blood. Preliminary data from a phase-1 dose-escalation study of up to 1x108 NK cells/Kg/dose and multiple dosing yielded promising results and a favorable safety profile (Ciurea SO.Blood.2017;130:18657). This report presents long-term follow-up from a phase-1/2 clinical trial in patients with high-risk myeloid malignancies (AML/MDS/CML) (clinicaltrials.gov NCT01904136) and a comparison with CIBMTR controls. Methods: Patients received conditioning with fludarabine 160 mg/m2, melphalan 140 mg/m2 and 2GyTBI, post-transplant cyclophosphamide-based GVHD prophylaxis and bone marrow graft from a haploidentical donor. Ex vivo expanded NK cells were generated from peripheral blood mononuclear cells of the same donor with a K562 feeder cells expressing mb-IL21 and 41BB and infused fresh on Day-2, and cryopreserved on Day+7 and +28 (up to Day+90). 1x108/Kg/dose was chosen for the phase 2 trial. An independent matched-pair analysis was done using controls from the CIBMTR database stratified by conditioning intensity. Results: 24/26 patients treated to date were evaluable (one short follow-up and one excluded as ineligible). 80% (19/24) of patients received all 3 doses of NK cells. The median age was 45 years (range 18-59), median follow-up was 43.6 months (range 15.1-60.9). Thirteen patients (54%) were females. 5 patients had donor-specific anti-HLA antibodies (DSA). The median HCT-CI was 2 (range 0-8), 12 patients (50%) had HCT-CI>3. 17 patients (72%) had AML/MDS and 7 (28%) advanced CML. Of AML/MDS patients, 10 (59%) had high-risk cytogenetics, 7 (41%) had measurable residual disease, 9 (53%) had intermediate/adverse-risk ELN2017 and 5 (29.4%) had primary induction failure. No infusion reactions or significant adverse events were observed to date. All patients (100%) achieved engraftment after a median of 19 days (range 14-42). The cumulative incidence (CI) of grade 2-4 aGVHD was 29.2% at Day100 and 41.7% at 1-year post-transplant. Only one patient developed severe grade 3-4 aGVHD and one patient had extensive cGVHD. Only one patient relapsed (a patient with DSA who did not receive desensitization prior to transplantation), 1-year CI of relapse was 5.9%. The CI of TRM at 1-year for patients without DSA was 21%. The median overall survival and progression-free survival (PFS) were not reached. The 1-year and 3-year PFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9% for patients without DSA, respectively (Figure 1). One-year and 3-years GRFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9%, respectively. An independent matched-pair analysis (at least 1:1) was conducted by CIBMTR after the first 18 patients treated on study in 07/2018 with RIC (N=57) or MAC (N=61) controls. The relapse was 1/18 vs 25/57 for RIC (p=0.037) and 15/61 for MAC (p=0.07), while the 1-year PFS was 82% vs 49% for RIC and 64% for MAC (p=0.21) (Figure 1). Updated results of this analysis will be presented at the meeting. Conclusions: Results from this long-term follow-up analysis confirm very low relapse rate and excellent GRFS after haploSCT for patients treated with high-doses of NK cells expanded with mbIL21 stimulation. A prospective multi-center phase 2 BMTCTN study will evaluate the safetly and efficacy of high doses of NK cells for the prevention of relapse in patents with AML/MDS receiving haploSCT. Figure 1 Disclosures Ciurea: Miltenyi: Research Funding; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Bashir:Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Pasquini:Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding; Medigene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Lee:Kiadis Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia in Era of Tyrosine Kinase Inhibitors -a Single Centre Experience from India

Background Transplant remains most curative option for patients with TKI resistant disease or in advanced phase of CML. We retrospectively analyzed transplant outcome of CML patients in era of TKI from our centre. Methods All patients who underwent allogeneic stem cell transplant for CML between Aug 2010 to Sept 2016 were included. Conditioning regimens included Flu-Mel (67.5%), Bu-Cy (10%), Flu- 7.2 Gy TBI (15%), or Flu-treo-2GyTBI (7.5%). For matched sibling (MSD) or unrelated donor (MUD) transplants, GVHD prophylaxes were cyclosporine (CsA) with methotrexate in 26(65%) or mycophenolate(MMF) in 8 (20%) patients respectively . Post transplant cyclophosphamide (PtCy) with CSA / tacrolimus with MMF was used in 6 (15%) patients who underwent haploidentical transplant (HIT) .Disease Risk Index (DRI), HCT-CI and EBMT scores at transplant were calculated for all . Overall survival (OS) was calculated from date of transplant to date of death or last follow up while relapse-free survival (RFS) was calculated till date of molecular relapse (>0.1% BCR-ABL),death or LFU if in MMR. Prognostic factors evaluated were duration from diagnosis to transplant ( 2 years), EBMT score (≤3 vs>3), acute and chronic GVHD, type of transplant and DRI index. Results Median age was 30 years (12-55) of which 30 (75%) were male. TKI failure was the commonest reason for transplant (95%) .T315I mutation was seen in 17.5% of patients . Twenty-six (65%) were in CP, 8 in AP and 6 in BC at diagnosis. The median EBMT and HCT-CI score were 3 and 2 respectively. Twelve (30%) patients had high DRI. MSD transplant was performed in 33 (82.5%), 6 (15%) underwent HIT and 1 MUD transplant. All except 1 patient received PBSC graft. Grade III/IV mucositis and diarrhea were seen in 19 (47.5%) and 4 (10%) patients respectively. Median time to neutrophil and platelet engraftment were 16 and 13.5 days respectively. Incidence of grade III/IV acute GVHD and chronic GVHD was 50% and 60% respectively. At 1 year post transplant >4.5 log reduction (DMR) was attained in 25 (62.5%) while 5 (12.5%) patients were in MMR. Five patients received DLI (3 patients for clinical relapse,2 for slippage of chimerism). Median follow up was 36 months. Non relapse mortality was seen in 8 (20%) patients. (GVHD-7, Myocarditis1). OS and RFS at 5 years were 70 % and 57 % respectively. In multivariate analysis for RFS, EBMT score≤ 3 and time from diagnosis to transplant > 2 years were independent prognostic factors for better RFS. For OS, presence of chronic and absence of acute GVHD were independent prognostic factors for better survival. Conclusion The long term survival in TKI resistant and advanced CML with transplant is promising. Along with other factors, transplant after 2 years from diagnosis was an independent prognostic factor for better survival contrary to transplant within 1 year of diagnosis in the pre TKI era .This may be due to better disease control with advent of TKIs.

Therapeutic Effects of Pretreatment with Tocovid on Oxidative Stress in Postischemic Mice Brain

Dietary supplement is an attempt to reduce the risk of ischemic stroke in high-risk population. A new mixed vitamin E-Tocovid that mainly contains tocotrienols other than tocopherol, attenuated the progression of white matter lesions by oral in humans. However, the effect of Tocovid on ischemic stroke has not been examined. In the present study, we assessed the therapeutic effects of Tocovid pretreatment on transient middle cerebral artery occlusion (tMCAO) in mice. After pretreatment with Tocovid (200 mg/kg/d) or vehicle for 1 month, 60-minute tMCAO was performed, and these mice were examined at 1 day, 3 days, and 7 days after reperfusion. We histologically assessed the effects of Tocovid pretreatment on the expressive changes of oxidative stress markers, cleaved caspase-3, and LC3-II after tMCAO in mice. We observed that Tocovid pretreatment significantly improved the rotarod time, reduced infarct volume, decreased the number of 4-HNE, nitrotyrosine, and 8-OhdG positive cells, inhibited advanced glycation end products biomarkers RAGE, CMA, and CML expressions, and increased Nrf2 and MRP1 levels with GSSG/GSH ratio decrease. Furthermore, Tocovid pretreatment greatly decreased cleaved caspase-3 and LC3-II expressions after tMCAO. The present study obviously demonstrated that Tocovid pretreatment showed neuroprotective effects against oxidative stress and at least in part by antiapoptotic/autophagic cell death in ischemic mice brain.

Haploidentical Donors in Addition to Transplantation in Chronic Phase Associate with Improved Gvhd-Free Relapse-Free Survival (GRFS) for Patients with Advanced CML

Introduction: Despite the successes of treatment with tyrosine kinase inhibitors (TKIs) in patients with CML, allogeneic hematopoietic stem cell transplantation (ASCT) continues to be a potentially curative option for patients with advanced disease of who fail TKI therapy. Here we analyzed outcomes of patients with advanced CML (aCML) (beyond first chronic phase-CP1) who received an ASCT at our institution to identify factors associated with improved survival.Methods:207 consecutive patients withaCML treated at The University of Texas MD Anderson Cancer Center after year 2000 were included. The median age was 44 years (range 2-70 years), 135 (65%) were male, 77% had less than 5% bone marrow (BM) blasts, 129 (65%) had persistentPh-chromosome positive, and 176 patients (85%) were less than a major molecular response at transplant. Forty of 114 tested patients (35%) had resistant BCR-ABL mutations and 10 patients (8.7%) had T315I mutation at transplant. Conditioning regimen wasmyeloablative (MAC) in 140 patients (68%). Donors were matched related (MRD), matched unrelated (MUD),haploidentical (HAPLO), mismatched unrelated (MMUD), umbilical cord blood (UCB) and 1Ag mismatched related (MMRD) in 79 (38%), 75 (36%), 18 (9%), 17 (8%), 11 (5%) and 7 (3%) patients, respectively. The median time from diagnosis to transplant was 27 months (range 1-318 months) while the median follow-up duration was 20 months (range 1-194 months).Results:At 30 days post-transplant, 180 of 200 tested patients (90%) and 134 of 201 tested patients (67%) achieved a complete cytogenetic and at least a major molecular response, respectively. The response to transplant by day 30assessment correlated significantly with the disease status before transplant. A higher percentage of patients who experienced cytogenetic response before transplant experienced molecular response post-transplant (77%) compared with those who did not (61%; p=0.027). For the entire group, the 1-year cumulative incidence (CI) of acute GVHD (aGVHD) grade II-IV and grade III-IV were 41% and 15%, respectively; 5-year CI of extensive chronic GVHD (cGVHD) was 31%.Haploidentical transplant patients had lesscGVHD compared with HLA matched donor transplants (14% vs. 32% for HLA matched transplants). The CI of non-relapse mortality at 100 days and 1 year was 14% and 30%, respectively. Sixty-five patients (31%) had molecular relapse after transplant, which correlated with the degree of disease control before transplant. The CI of cytogenetic and molecular relapse at 5 years was 22% and 31%, respectively.Overall the 5-year survival (OS), progression free survival (PFS) and GVHD-free, relapse-free survival (GRFS)was49%, 34%, and 22%, respectively. Adjusting for all significant measures, percentage of BM blasts before transplant and donor type were significantly associated with PFS and GRFS (Table1, Figure 1).Haplodenticaltransplant patients had longer PFS and GRFS compared with other donor types including matched related or unrelated donor (5-year GRFS for HAPLO, MRD, MUD, MMUD, UCB and MMRD were 53%, 19%, 23%, 29%, 9%, and 0%, respectively; p=0.033) (Table 1, Figure 1). Cytogenetic and molecular response before transplant as well as year of transplant did not predict survival after transplant.Conclusions: ASCT is curative for a proportion of patients withaCML. PFS and GRFS are favorably influenced by percentage of BM blasts and donor type, withhaploidentical donor having at least as good outcomes as HLA matched donors, while molecular and cytogenetic response before transplant do not appear to correlate with survival post-transplant. [Display omitted] [Display omitted] DisclosuresCortes:Arog: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Research Funding; Ambit: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties. Ciurea:Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership.

Failure to Achieve Early Molecular Milestone within 3 Months Is Associated with Higher Risk of Relapse and Worse Survival after Allogeneic Hematopoietic Stem Cell Transplant for Chronic Myeloid Leukemia Patients, Especially after Tyrosine Kinase Inhibitor Failure

BACKGROUNDEarly molecular response (EMR) of less than 10%IS of BCR-ABL transcript level at 3 months has become widely accepted as the earliest milestone in CML treatment. Close monitoring and switch of TKI therapy is recommended if the patient continues to fail to achieve less than 10%IS at 6 months. Thus EMR has guided our treatment intervention in the high risk group of patient before they progress to advanced stage CML. After multiple TKI therapy failure, the only available curative treatment is allogeneic hematopoietic cell transplantation (HCT). Around 20-30% of patients still progress or relapse after HCT. Accordingly, there is obligatory requirement for early molecular monitoring to guide pre-emptive treatment to reduce the risk of imminent relapse. The current study reviewed and analyzed transplant outcomes in 223 CML patients.METHODSA total of 223 patients were reviewed who received HCT across 6 transplant centers in Canada between 2002 and 2014. According to their response to TKI therapy and disease state prior to HCT, patients were divided into 4 groups: TKI resistance (n=132), TKI intolerance (n=29), TKI naïve/response chronic phase (CP) (n=27) or advance disease stage but TKI responsive (n=35). Using the binary recursive partitioning method with BCR-ABL transcript levels taken within 3 months post-HCT, patients were further divided into 3 groups: 1) those failing to achieve less than 1.3 log reduction (Group1.3), 2) the group achieving between 1.3 and 4.4 log reduction (Group1.3-4.5), and 3) the patients who achieved 4.5 log reduction or deeper response (Group4.5). According to the 4 groups stratified by TKI response/disease risk or to the 3 groups based on BCR-ABL transcript level within 3 months, transplant outcomes were analyzed with respect to overall survival (OS), non-relapse mortality (NRM), relapse and incidence of complete hematologic response (CHR) loss. Post-HCT TKI therapy for relapsed CML was also reviewed and analyzed for response/long-term outcomes.RESULTSThe OS was the highest in TKI naïve/responsive CP group (88.6% at 5 years), followed by TKI intolerance (70.6%), advanced disease group responsive to TKI therapy (63.4%) and the lowest in TKI resistance group (50.3%; p=0.003 among 4 groups). The incidence of relapse was high in TKI resistance group (30.6% at 5 years) and in advanced disease group (30.6%) compared to TKI intolerance group (16.0%) or TKI naïve/responsive CP group (12.1%; p=0.067).According to BCR-ABL transcript levels 3 months post-HCT, Group1.3 showed the lowest rate of molecular response (MR) 4.5 (7.1% at 2 years) compared to 49.9% in Group1.3-4.5 vs 72.7% in Group 4.5 (p<0.001). Group1.3 also showed the highest relapse rate of 78.6% at 5 years, compared to 23.9% in Group 1.3-4.5 and 26.4% in Group 4.5 (p<0.001).In multivariate analysis for OS, Group1.3 increased the risk of death by 2.3 fold in addition to advanced disease at diagnosis (HR 2.5), acute GVHD (HR 2.3) and chronic GVHD (HR 0.28). For relapse, Group1.3 increased the risk of relapse by 6.6 fold, while chronic GVHD decreased it by 57% (HR 0.43). However, none of TKI failure, disease stage prior to HCT, additional cytogenetic abnormalities in Ph+ clone, clonal evolution in Ph neg clone, or ABL1-kinase domain mutation was found to be prognostic.Of 223, 61 patients experienced relapse in 10 months post-HCT, among which 47 patients were treated with TKI therapy. Of 45 evaluated, 26 patients (57.8%) achieved molecular response. Response was lower in the group with CHR loss as 34.6% than those with MR2 loss (100%) or MR3 loss (88.2%; p<0.001). For OS after post-HCT TKI therapy (OSTKI), OSTKI was the highest in the group with MR3 loss (81.9%), followed by those with MR2 loss (66.7%), then lowest with CHR loss (27.0%; p<0.001). Multivariate analysis confirmed that relapse type is an independent risk factor for response (p=0.002) and for OSTKI (p=0.004). The group with hematologic relapse as CHR loss had 8.9 times higher risk of death compared to those with loss of MR2/MR3.CONCLUSIONThe present study confirms that the EMR within 3 months post-HCT is associated with transplant outcomes: failure to achieve 1.3 log reduction of BCR-ABL transcripts in 3 months post-HCT for CML, significantly increases the risk of relapse. Thus pre-emptive post-HCT TKI therapy is warranted in failing patients to reduce imminent risk of relapse after allogeneic HCT in CML patients. [Display omitted] DisclosuresSavoie:Jazz: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Lundbeck: Consultancy. Bence-Bruckler:Lundbeck: Membership on an entity's Board of Directors or advisory committees. Lalancette:Celgene: Honoraria; BMS: Honoraria. Hillis:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.

Long-Term Follow-up of the Efficacy and Safety of Ponatinib in Philadelphia Chromosome-Positive Leukemia Patients with the T315I Mutation

Long-Term Follow-up of the Efficacy and Safety of Ponatinib in Philadelphia Chromosome-Positive Leukemia Patients with the T315I Mutation

Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180−270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation.

MS4A3 Improves Imatinib Response and Survival in BCR-ABL1 Primary TKI Resistance and in Blastic Transformation of Chronic Myeloid Leukemia

Background: Mutations in the BCR-ABL1 kinase domain are a well-documented mechanism of resistance to tyrosine kinase inhibitors (TKIs), but less is known about primary resistance independent of BCR-ABL1 kinase activity. We reported a gene expression classifier of TKI-naïve CD34+ cells from chronic phase chronic myeloid leukemia (CP-CML) patients that predicts cytogenetic response to imatinib (McWeeney et al. Blood 2010). The expression signature associated with primary cytogenetic failure showed overlap with previously reported signatures of blast phase CML (BP-CML), suggesting that primary TKI resistance and advanced disease are biologically similar.Results: To identify critical genes involved in primary TKI resistance, we performed principal component analysis on the expression signature and identified the hematopoietic cell cycle regulator, MS4A3, as a key factor within this classifier. Importantly, low MS4A3 expression not only correlated with primary TKI resistance, but also with shorter overall survival (p<0.01), prompting us to study the role of MS4A3 in more detail. Since the signatures for primary cytogenetic failure and BP-CML overlapped, we next assessed whether MS4A3 expression was downregulated in BP-CML versus CP-CML. qRT-PCR confirmed that MS4A3 mRNA levels are markedly reduced (by >92%) in CD34+ cells from BP-CML patients (n=17; p<0.01) versus CP-CML patients (n=23) and normal controls (n=3). There was no significant difference between normal and chronic phase CD34+ cells, suggesting that MS4A3 is specifically downregulated upon CML blastic transformation. Microarray data from Oehler et al. (unpublished observations) and Zheng et al. (Leukemia 2006) also showed that MS4A3 mRNA levels are reduced in CD34+ cells from BP-CML patients (n=16; p<0.001) compared to CP-CML patients (n=19). Immunoblot analyses confirmed that MS4A3 protein was detectable in CD34+ cells from newly diagnosed CP-CML patients, but not in samples from patients with primary resistance who failed multiple TKIs but lack clinically relevant BCR-ABL1 mutations. Finally, in CP-CML samples from newly diagnosed patients, MS4A3 mRNA levels are 12-fold reduced in primitive CD34+38- stem cells compared to more committed CD34+38+ progenitor cells (n=3; p<0.05), which are innately resistant to BCR-ABL1 inhibition. Consistent with BCR-ABL1 kinase independence, MS4A3 mRNA and protein levels were unaffected by ex vivo TKI treatment.MS4A3 expression is also low in BP-CML cell lines, including K562, KYO-1, BV-173, KCL-22, and KU-812, with the notable exception of LAMA-84 cells. Thus, to understand the functional role of MS4A3 for TKI resistance, we introduced a doxycycline-inducible shRNA targeting MS4A3 (shMS4A3) into LAMA-84 cells. qRT-PCR confirmed 50-90% MS4A3 knockdown in the presence of doxycycline (0.1 µg/mL). Consistent with its role as a tumor suppressor, MTS assays revealed that MS4A3 knockdown increased the imatinib IC50 (n=3; p<0.05) and abolished the effects of imatinib in colony formation assays (n=2; p<0.05). We next assessed the effects of shMS4A3 in CD34+ cells from newly diagnosed CP-CML patients. qRT-PCR confirmed ~50% MS4A3 knockdown in primary cells. Despite the incomplete knockdown, shMS4A3 enhanced colony formation in the presence of imatinib in a dose-dependent manner (n=4; p<0.00001), and abolished imatinib-induced apoptosis (n=3; p<0.001). We also assessed the effects of ectopic MS4A3 expression in CD34+ cells from advanced phase CML (AP-CML) patients. qRT-PCR confirmed >2-fold upregulation of MS4A3. As expected, ectopic MS4A3 reduced colony formation by 55% in AP-CML (n=2; p<0.01), and enhanced sensitivity to imatinib-induced apoptosis by 35% (n=2; p<0.01). Neither shMS4A3 nor ectopic MS4A3 had any effect on survival of normal cord blood CD34+ cells (n=2).Conclusion: Our results suggest that MS4A3 is a tumor suppressor protein in CML that governs TKI responsiveness and is regulated in a BCR-ABL1 kinase-independent manner. MS4A3 loss confers TKI resistance to CP-CML patients destined to exhibit primary cytogenetic failure, and in BP-CML patients with refractory resistance. MS4A3 may also contribute to the innate resistance of primitive CML stem cells. Studies to identify the mechanism of MS4A3 downregulation in TKI resistance and how its loss biochemically impairs TKI response is currently underway and will be reported. DisclosuresAgarwal:CTI BioPharma: Research Funding. Deininger:BMS: Other: Consulting & Advisory Role, Research Funding; Novartis: Other: Consulting or Advisory Role, Research Funding; Celgene: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; ARIAD Pharmaceutical Inc.: Other: Consulting or Advisory Role; Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role.

Disease-Free Survival in Adult Patients with Acute Leukemia and Advanced CML Supports Use of Double-Unit Cord Blood Grafts As an Immediate Alternative to 8/8 HLA-Matched Unrelated Donors (URD)

Background: Double-unit cord blood transplantation (DCB-T) is a rapidly available alternative to unrelated donor transplantation (URD-T) for patients with high-risk acute leukemia or advanced CML. Retrospective analyses in adult DCB-T suggest that double-unit CB grafts may be associated with improved disease-free survival (DFS). However, the prioritization of URD-T vs DCB-T is controversial.Methods: We evaluated 175 consecutive adult allograft recipients (120 URD-T and 55 DCB-T) aged 16-60 years transplanted 10/2005-11/2012 for acute leukemia in morphologic remission or aplasia (113 AML/ biphenotypic, 50 ALL), or advanced CML (n = 12). URD grafts were 7-8/8 HLA-matched (74 8/8, 46 7/8). CB grafts were 4-6/6 donor-recipient HLA-matched (4 6/6, 51 5/6, 55 4/6). All patients received either high dose or reduced intensity myeloablative conditioning. The majority of URD-T recipients (n = 111, 93%) received T-cell depleted (TCD) grafts with rabbit ATG, whereas GVHD prophylaxis for DCB-T was calcineurin-inhibitor/mycophenolate mofetil.Results: The median ages of URD-T (43 years) and DCB-T (42 years) recipients were similar (p = 0.713). Distributions of gender, recipient CMV positivity, HCT-CI scores, time from diagnosis or relapse to transplant, diagnoses, disease risk, and percentage of patients with minimal residual disease pre-transplant were also similar. Neutrophil engraftment was slower in DCB-T (95%, median 24 days) than URD-T (100%, median 11 days) (p <0.001). While the incidence of grade II-IV acute GVHD at day 100 was lower in TCD URD-T recipients (15%) than in unmodified URD-T (56%) and DCB-T (55%), p = 0.002, the incidence of day 100 grade III-IV acute GVHD was similar in TCD URD-T, unmodified URD-T, and DCB-T recipients (p = 0.794). With a comparable survivor follow-up [URD-T median 51 months (range 15-99) vs DCB-T median 46 months (range 15-92)], transplant-related mortality was similar (3-year estimates: URD-T 25% vs DCB-T 24%, p = 0.838) whereas the relapse risk was decreased after DCB-T (3-year estimates: URD-T 23% vs DCB-T 9%, p = 0.008). Overall, the 3-year DFS after URD-T was 52% and 68% after DCB-T (p = 0.056). When split into 3 groups, the 3-year DFS was 59% in 8/8 URD-T, 40% in 7/8 URD-T, and 68% in DCB-T, p = 0.043 (Figure). Multivariate analysis was performed to determine risk factors for disease relapse or death in the 175 patients (Table). Female gender (HR 1.65, p = 0.029), diagnosis of ALL (HR 2.11, p = 0.002), and mismatched URD-T (HR 1.97, p = 0.027) were each significantly associated with treatment failure.Conclusions: DCB-T can achieve favorable DFS in adults with acute leukemia and CML with low relapse rates. In this series, multivariate analysis demonstrated that mismatched URD-T was independently associated with lower DFS. Our findings support use of DCB-T as an immediate alternative for high-risk acute leukemia and advanced CML in adult patients without a readily available 8/8 allele HLA-matched unrelated volunteer donor. This could have the additional benefit of speeding time to transplant in high-risk patients.TableVariableMultivariateHR (95% CI)P-valueMale FemaleReference 1.65 (1.05-2.59)0.029 Recipient CMV Negative Recipient CMV PositiveReference 1.34 (0.85-2.12)0.201HCT-CI score 0-2 HCT-CI score > 3Reference 1.56 (0.98-2.47)0.059AML/CML ALLReference 2.11 (1.30-3.41)0.002DCB-T 8/8 URD-T 7/8 URD-TReference 1.32 (0.72-2.41) 1.97 (1.08-3.60)- 0.365 0.027 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Follow-up Results after Imatinib Discontinuation in Chronic Myeloid Leukemia Patients with Undetectable Minimal Residual Disease

IntroductionImatinib (IM) is an effective treatment in patients with chronic phase chronic myeloid leukemia (CML-CP). In the previous report (Leukemia research, 2012;36:689-693), we demonstrated that IM could be discontinued in CML patients achieved undetectable minimal residual disease (UMRD) after the treatment of front-line IM therapy. These observations were confirmed by prospective STIM1 and TWISTER studies. However, in both studies, approximately half of patients were treated with front-line interferon therapy, which might be a confounding factor when considering the impact of prior interferon on treatment free remission (TFR) in the previous IM discontinuation studies. Thus, the aim of this study was to investigate the long-term outcomes of IM discontinuation in patients with CML-CP, who have treated with front-line IM therapy and achieved UMRD.Patients and methodsWe consecutively enrolled patients with CML-CP, discontinued IM therapy after achieving UMRD for at least 12 months in 2 Korean institutions from June 2009 to Jan 2013. Patients with a prior history of any other treatment (>1 months) for CML before IM administration were excluded. UMRD was defined by undetectable levels of BCR-ABL transcript by RQ-PCR with sensitivity of at least 0.0046%IS. After discontinuation, BCR-ABL/ABL ratio was monitored by RQ-PCR monthly during the first 6 months and every 3 months thereafter, and molecular relapse was defined by detectable levels of BCR-ABL transcript in two successive assays.ResultsNineteen patients (8 male, 11 female) with a median age of 52 years (range, 29-78) were included. The reasons for discontinuing IM were shared decision between physicians and patients with long undetectable BCR-ABL transcript (n=9), chronic adverse events of IM (n=6), patient’s request (n=3), and wish for pregnancy (n=1). At initial diagnosis, the Sokal score was low to intermediate in 11 patients and high in 8 patients. All patients started IM at a dose of 400mg/day and median interval between IM initiation and UMRD was 21.5 months (range, 7.0-61.9). IM therapy was then maintained during a median of 34.8 months (range, 12.1-72.4).With a median follow-up of 52.1 months (range, 17.5-60.5), the overall probability of UMRD persistence at 4-year was 22.1% (95% CI, 11.6-32.6). Fourteen patients (73%) lost UMRD after a median of 4.0 months (range, 1.1-22.8). 12 patients relapsed within first 9 months and 2 late relapse were identified at 20.5 and 22.8 months, respectively. No patients included in this analysis were progressed to advanced stage CML or died. IM therapy was resumed in all patients with molecular relapse, but 2 patients were switched to dasatinib owing to chronic adverse events of IM. At the time of this analysis, all patients were still sensitive to IM and dasatinib therapy. 12 patients re-achieved UMRD and 2 patients maintained stable major molecular response. In univariate analysis for molecular relapse, high risk of Sokal score (P<0.001), ≥24 months of interval between IM initiation and UMRD (P=0.016), and <34.8 months of duration of IM therapy after UMRD achievement (P=0.029) were significantly associated with frequent molecular relapse.ConclusionThis study represents that IM discontinuation in patients who have received front-line IM therapy and achieved UMRD would be feasible, as approximately one-fourth of these patients could enjoy long-term TFR. Moreover, no molecular relapse was observed after 2 year of IM discontinuation. Although the Sokal score, time to deep molecular response, and duration of IM therapy were suggested as clinical factors for predicting molecular relapse in this analysis, further studies would be necessary to confirm the results in this population. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Long-Term Follow-Up (f/u) of ENESTnd

Efficacy and Safety of Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Long-Term Follow-Up (f/u) of ENESTnd