Early Phase Chronic Myeloid Leukemia Research Articles

Phase 2 Study of Dasatinib with and without Venetoclax in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECP-CML)

Background Treatment-free remission (TFR) is a therapeutic goal for patients with ECP-CML once patients maintain a deep molecular remission (DMR) on tyrosine kinase inhibitors (TKIs). Only a fraction of patients (pts) achieved sustained (3+ years) molecular remission with 4.0- to 4.5-log reduction (MR4.5). Preclinical studies showed that BCL-2 is a key survival factor for CML stem/progenitor cells. Therefore, the combination of TKIs and venetoclax, targeting BCR::ABL1 and BCL-2, has the potential to significantly improve DMR and subsequently the rates of TFR. The aim of this study is to evaluate the safety and efficacy of the combination. Methods Patients with ECP-CML or accelerated phase (AP; defined by clonal evolution only) were eligible; pts with < 1 month of prior TKI therapy were eligible. Pts received single-agent dasatinib 50 mg/d for the first 3 months. From Month 4 and onwards, venetoclax was administered from Days 1 to 14 each month concomitantly with dasatinib for a total of 3 years. The first 16 patients received venetoclax 200 mg/d, with a rapid ramp-up starting 50 mg on Day 1, then 100 mg on Day 2, then 200 mg daily on Day 3 and onwards. Due to neutropenia observed with continuous dose of venetoclax 200 mg/d, the protocol was ameded: from patient #17 and onwards, venetoclax was administered at 200 mg/d for 14 days per month and upon achievement of MR4.5, venetoclax was reduced to 100 mg/d for 7 days per month. After 3 years of combination, patients received single-agent dasatinib. TFR was offered after ≥ 3 years of DMR. The primary endpoint was the rate of major molecular response (MMR) by 12 months of the combination. The secondary endpoints were the 12-month rate of MR4.5 and the cumulative overall rate of MR4.5; the rates of MR4.5 at 6-, 12-, 18-, 24, and 36-months of the combination; the proportion of patients with sustained MR4.5 of 3 years and more; the TFR rate; overall survival; and the safety of the combination. Cumulative response rates were calculated with treatment failure as a competing event. Failure-free survival (FFS) was calculated from the initiation of therapy to loss of major cytogenetic response (MCyR), transformation to AP or blast phase, discontinuation of therapy for any reason except of TFR, or death. Results Sixty-five pts were enrolled and treated between April 2018 and August 2021. The median age at treatment initation was 46 years (range, 23-73) and 57% of the pts were females. Twenty-one (32%) pts had splenomegaly, 46 (71%) had low Sokal risk disease and 3 (5%) had high Sokal risk disease (Table 1). By 12 months of the combination, 85% of the pts had achieved MMR or deeper response. The median time to MMR, MR4, and MR4.5 were 6.2 months, 13 months, and 23.9 months from the time of TKI start, respectively. After a median follow-up of 25.7 months (range, 8.7-48.1), two pts discontinued therapy due to adverse events (GI intolerance, and pleural effusion); the 2 -year FFS was 96%. One pt switched TKI therapy due to the lack of 18-month complete cytogenetic response (CCyR); no loss of CCyR, transformation, or death was observed. We then compared the outcomes with the combination to the outcomes of 85 pts treated with single-agent dasatinib. From the start of TKI therapy, the 12-month cumulative MMR rates were 78% and 79% in the dasatinib single-agent and dasatinib + venetoclax groups, respectively. The cumulative 24-month rates of CCyR, MMR, MR4, and MR4.5 are summarized in Table 2. In the dasatinib single-agent group, 3 pts switched TKI therapy due to the lack of 12-month MCyR, 18-month CCyR, and the acquisition of ABL1 mutation (1 each); 3 pts switched TKI therapy due to loss of CCyR; 2 pts died during therapy (deaths unrelated to CML). Within one year of therapy, the incidence of grade 1/2 neutropenia (absolute neutrophil count, below lower range of normal to 1,000 x10 9/L) was 21% and 52% in the dasatinib single agent and dasatinib + venetoclax groups, respectively ( P<0.001); the incidence of grade 3/4 neutropenia (absolute neutrophil count, below 1,000 x10 9/L) was 8% and 17%, respectively ( P<0.001). There was no incidence of neutropenic fever in the dasatinib + venetoclax. Conclusion The combination of dasatinib 50 mg/d and venetoclax is safe and effective in pts with ECP-CML. With a median follow-up of 2 years, the cumulative resposne of dasatinib + venetoclax is similar to that of dasatinib single-agent without adding significant toxicities. Further follow-up is needed for the evaluation of TFR.

Evaluating the Role of Lower Dose Dasatinib in Newly Diagnosed Early Chronic Phase-Chronic Myeloid Leukemia (CML-CP)

Introduction: Dasatinib is a potent tyrosine kinase inhibitor (TKI) of BCR-ABL . It is currently approved for the treatment of all phases of CML. Approved dose in the chronic phase is 100mg daily. This is however associated with notable side effects mainly myelosuppression and pleural effusion, leading to dose reductions/interruptions. Lower doses of dasatinib have been shown to be effective in elderly CML patients.Objective: To evaluate the efficacy and toxicity profile of lower dose dasatinib, at 50 mg orally daily in patients with early CML-CP.Methods: All patients presenting to our institution in early CML-CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884).Results: From March 2016 to July 2017, 56 patients have been enrolled. Median age is 46 years (range 22-80). Patients categorized by Sokal risk are: low 34; intermediate 16 and high 6. Nine patients received prior TKI (for <= 30days): dasatinib 5; imatinib 3; nilotinib 1. Response to lower dose dasatinib is shown in Table 1.At 3 months, 93% patients had achieved early molecular response (BCR-ABL PCR <10%) to therapy. Ten patients had BCR-ABL PCR < 1% (equivalent to CCyR) at 3 months but tested positive by FISH as shown in Table 2. At 6 months, 7 of these 10 patients that were FISH positive at 3 months, achieved CCyR (FISH 0%); of these 7 patients, 6 patients achieved a MMR. Three of the remaining 10 patients that were FISH positive at 3 months, have not yet reached (NR) the 6 month follow-up.Nine patients had treatment interruption of up to 14 days in the 1st 3 months of therapy: gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 2. None of these patients required dose modification and tolerated dasatinib once it was resumed.Seven of these 9 patients with dose interruption have achieved early response to therapy while 2 patients have not yet reached the 3 month follow-up. Therapy was discontinued in 1 patient secondary to subdural hemorrhage (traumatic), while 1 patient at 6 months was deemed a failure due to lack of cytogenetic response and BCR/ABL PCR > 10%, requiring an increase in dasatinib dose to 100mg daily. None of the patients have developed pleural effusion so far.Conclusion: Dasatinib at 50 mg daily dose is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule option in CML. [Display omitted] DisclosuresCortes:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Pemmaraju:Cellectis: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Stemline: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria. Bose:Incyte Corporation: Honoraria. Thompson:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding.

Imatinib in Children with Chronic Myeloid Leukemia in Chronic Phase: Long-Term Results of the French National Phase IV Trial

Because of the rarity of Chronic Myeloid Leukemia (CML) in children and adolescents, only few studies reported on efficacity and tolerance of imatinib in the pediatric population and scant data are available regarding long-term follow-up. The aim of our analysis was to assess, the long-term efficacity and safety of imatinib in children with CML in early chronic phase included in the French multicentric prospective Glivec Phase IV trial (Millot et al, J Clin Oncol 2011). Methods: Children aged 0 to 18 years with newly diagnosis CML in chronic phase were eligible to received daily imatinib 260 mg/m² according the trial. Long-term analysis included overall survival (OS), progression-free survival (PFS), response to treatment and adverse events. Results: Between March 2004 and December 2008, 44 patients (median age 13.4 years; range 0.8 - 16.7 years) were included in the trial. As of April 2019, with a median follow-up of 10.6 years (range 1.8 - 13.4 years), 2 patients (pts) progressed to blastic crisis and only one death was recorded. The median age was 21.8 years (range 9.3 - 28.8 years) at the last follow-up. The median duration of imatinib therapy was 10.5 years (range 0.2 - 12.5 years) for the entire cohort. To date, 13 pts (29.5%) are still treated with imatinib. Thirty-one pts (70.5%) had discontinued first line treatment with imatinib after a median time of treatment of 2.4 years (range 0.2 - 10.6 years) for the following reasons: 10 pts did not achieve major molecular response (MMR), 1 pt developed blast crisis, 2 pts had unsatisfactory level of molecular response (MR) according to the clinician, 10 pts lost their response (loss of complete hematological response n=1, complete cytogenetic response [CCR] n=6 and MMR n=3), 4 pts attempted treatment free remission (TFR), 3 pts were intolerant to imatinib and 1 pt stopped because of pregnancy. Among these 31 pts who discontinued imatinib, 2 pts are still in TFR, and 29 pts switched to a second line therapy: second generation tyrosine kinase inhibitors (2TKI) (n=25), allogeneic hematopoietic stem cell transplantation (HSCT) (n=3), polychemotherapy (n=1). Sixteen of these 31 pts (51.6%) required subsequent lines of therapy including a second pt who transformed to blastic crisis under a second line therapy with dasatinib. Overall 11 pts (25%) underwent HSCT. Overall, regarding the best response, during the study follow-up 11 pts (25%) achieved MMR after a median time of 2.3 years (range 0.8-5.1), 7 pts (13.6%) achieved MR4 after a median time of 5.1 years (range 2.5-7.8), 25 pts (56.8%) achieved MR4.5 after a median time of 2.92 years (range 1.1-10.4) and 1 pt (2.3%) achieved CCR only. At last follow-up, 43 out the 44 pts were alive : 3 pts (7%) were in CCR, 12 pts (27.9%) in MMR, 6 pts (13.9%) in MR4 and 22 pts (51.2%) in MR4.5. Among the 13 pts still treated with imatinib, 1 pt (7.7%) was in CCR, 6 pts (14%) in MMR, 3 pts (23.1%) were in MR4 and 3 pts (23.1%) in MR4.5. Among the 11 transplanted patients, all pts except one are alive, in at least MR4.5. The death was related to post transplant infection. On an intention to treat basis, the 10-year OS of 44 patients treated was 97.7% (CI 95% 93.3-100). The 10-year PFS was 95.5% (CI 95% 89.3-100). We collected also the long-term safety of imatinib in the 25 pts who have received this therapy for more than 4 years. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after 4 years of imatinib. There is a decrease in the frequency of hematologic and extra hematologic sides effects reported during the first year and those reported after the fourth year of treatment with imatinib: musculoskeletal events 80 vs 24% (p&lt;0,0001), abdominal pain 44% vs 16% (p=0,03), nausea 48% vs 16% (p=0,02), diarrhea 24% vs 0% (p=0,01) and neutropenia 84% vs 28% (p&lt;0,0001), respectively. Conversely, the incidence of lymphopenia appeared with duration of imatinib treatment (p=0,04). Conclusion: With more than 10 years of follow-up, we showed that imatinib remains effective in one third of children included in the Glivec phase IV study with acceptable adverse effects and a low impact over time. Despite the notable proportion of switches, the OS and the PFS remain satisfactory in this pediatric cohort. Disclosures No relevant conflicts of interest to declare.

The AHI-1-BCR-ABL-DNM2 Complex Mediates Mitochondrial Dynamics in Drug-Resistant BCR-ABL+ Cells

Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 oncoprotein with constitutively active protein-tyrosine kinase activity, perturbing multiple signaling pathways. Although therapies with tyrosine kinase inhibitors (TKIs) can effectively treat early phase CML, relapses and emergence of TKI resistance are problematic, due to BCR-ABL kinase domain mutations and TKI unresponsive quiescent leukemic stem cells (LSCs). These observations point towards a need for alternate treatment strategies to prevent the development of resistant LSCs. We previously demonstrated that Abelson helper integration site-1 (AHI-1) is a highly deregulated protein in CML LSCs and that its WD40-repeat domain physically interacts with BCR-ABL, enhancing leukemia-initiating activity. AHI-1 also contains an SH3 domain, which mediates TKI resistance in LSCs. This domain interacts with dynamin-2 (DNM2) and forms a complex with BCR-ABL, to enhance the phosphorylation and activity of DNM2. The AHI-1-BCR-ABL-DNM2 complex is shown to regulate leukemic properties in patient LSCs, including increased ROS production, endocytosis and autophagy. Interestingly, deletion of the Ahi-1 SH3 domain (Ahi-1 SH3Δ) results in a defect in Ahi-1 localization, with most being present in the nucleus. To test whether Ahi-1 SH3 domain activity directly affects cytoplasmic anchoring and localization, we have generated two Ahi-1 mutants, using site-directed mutagenesis: a mutation in the key tryptophan residue (W939A) involved in SH3 domain binding and in a non-conserved surface residue (M906A), as a negative control, based on the crystal structure of the AHI-1 SH3 domain. Interestingly, the cytoplasm-to-nucleus signal ratio of Ahi-1 W939A was significantly reduced compared to the negative control or wildtype Ahi-1, as assessed by immunofluorescence and confocal microscopy (70% reduction, p&amp;lt;0.0001), indicating that changes in localization of Ahi-1 SH3Δ may result in disruption of the complex and allow for new interactions with nuclear proteins. Investigating changes in the proteome may help uncover downstream effects of the AHI-1-BCR-ABL-DNM2 complex and its biological role in mediating TKI resistance. Advanced antibody microarray analysis was then used to investigate differences in the proteome and phosphorylation landscape of BCR-ABL+ cells co-transduced with wildtype Ahi-1 or Ahi-1 SH3Δ. This system quantifies the differences in expression and phosphorylation states of key signaling proteins simultaneously, using 878 antibodies in duplicate. Twenty leads were identified by the following criteria: a large signal difference of at least 1.5-fold change, high signal strength for high expression, and low error between duplicates. These leads were validated by Western blot analysis and several of them were confirmed. Particularly, phosphorylation of cyclin-dependent kinase 1 (CDK1), a key player in cell cycle control and mitochondrial dynamics, was greatly reduced in cells expressing wildtype Ahi-1 compared to Ahi-1 SH3Δ, indicating that AHI-1-mediated phosphorylation changes in CDK1 may contribute to regulation of mitochondrial functions. Indeed, BCR-ABL-transduced cells co-expressing wildtype Ahi-1 showed increased mitochondria potential in response to TKI treatment or serum starvation, in MitoTracker analysis (p&amp;lt;0.05). However, this was not observed in BCR-ABL-transduced cells co-expressing the Ahi-1 SH3Δ mutant. A similar trend was also observed in immunofluorescence confocal microscopy analysis of the mitochondrial importer receptor, TOM20. To further study the role of DNM2 in mediating mitochondrial dynamics associated with AHI-1 and BCR-ABL, CRISPR-Cas9 mediated DNM2 knockdown was performed in TKI-resistant cells, using two different DNM2-targeting guide RNAs; these resulted in significant reduction in DNM2 (78% &amp; 75%) in Western blot analysis. The knockdown cells showed a reduction in viability (60% reduction) and increased sensitivity to TKI treatment compared to the control (90% vs. 30% reduction) after 48 hours and changes in mitochondrial activity were also observed in these cells. These results support a role for mitochondrial dynamics in the AHI-1-BCR-ABL-DNM2 complex-mediated TKI response and that targeting key biological processes regulated by the AHI-1-BCR-ABL-DNM2 complex and its pathways may lead to new therapeutic strategies to overcome TKI resistance in CML. Disclosures Pelech: Kinexus Bioinformatics Corporation: Equity Ownership.

Jak-2 and Nfkbia Gene Expression Play a Strategic Role in Chronic Myeloid Leukemia (CML) Molecular Response during Early Nilotinib Treatment: The PhilosoPhi34 Data

Jak-2 and Nfkbia Gene Expression Play a Strategic Role in Chronic Myeloid Leukemia (CML) Molecular Response during Early Nilotinib Treatment: The PhilosoPhi34 Data

DNA methylation profiling reveals a pathological signature that contributes to transcriptional defects of CD34+ CD15- cells in early chronic-phase chronic myeloid leukemia.

Despite the high efficiency of tyrosine kinase inhibitors (TKI), some patients with chronic myeloid leukemia (CML) will display residual disease that can become resistant to treatment, indicating intraclonal heterogeneity in chronic‐phase CML (CP‐CML). To determine the basis of this heterogeneity, we conducted the first exhaustive characterization of the DNA methylation pattern of sorted CP‐CML CD34+CD15− (immature) and CD34−CD15+ (mature) cells at diagnosis (prior to any treatment) and compared it to that of CD34+CD15− and CD34−CD15+ cells isolated from healthy donors (HD). In both cell types, we identified several hundreds of differentially methylated regions (DMRs) showing DNA methylation changes between CP‐CML and HD samples, with only a subset of them in common between CD34+CD15− and CD34−CD15+ cells. This suggested DNA methylation variability within the same CML clone. We also identified 70 genes that could be aberrantly repressed upon hypermethylation and 171 genes that could be aberrantly expressed upon hypomethylation of some of these DMRs in CP‐CML cells, among which 18 and 81, respectively, were in CP‐CML CD34+CD15− cells only. We then validated the DNA methylation and expression defects of selected candidate genes. Specifically, we identified GAS2, a candidate oncogene, as a new example of gene the hypomethylation of which is associated with robust overexpression in CP‐CML cells. Altogether, we demonstrated that DNA methylation abnormalities exist at early stages of CML and can affect the transcriptional landscape of malignant cells. These observations could lead to the development of combination treatments with epigenetic drugs and TKI for CP‐CML.

The Analysis of 12-Year Overall Survival in Non-Selected Patients with Chronic Myeloid Leukemia with Tyrosinekinase Inhibitors Therapy in Routine Practice

Abstract Background: The analysis of overall survival (OS) of patients with a chronic myeloid leukemia (CML) who were receiving treatment with tyrosinekinase inhibitors (TKI) - imatinib, nilotinib, dasatinib in routine practice is a promising direction. Aims: To assess the efficacy of the 1- nd (imatinib) and 2-nd (nilotinib, dasatinib) lines therapy of TKI - OS in non-selected patients with a CML in routine practice. Methods: The study included non-selected group of 88 patients with CML in different phase: 44 patients with CML in early chronic phase (ECP), 44 patients with CML in late chronic phase (LCP) who have received early in the disease the imatinib in the 1-nd line therapy in routine practice. We have estimated OS during 12 years of treatment with TKI, defined by standard statistical methods. Results: 31 (70.5%) of 44 patients in ECP were alive by 12 years of therapy of TKI. 23 (74.2%) of 31 patients receiving imatinib, 8 (25.8%) - nilotinib in the 2-nd line therapy. 13 (29.5%) of 44 patients died, 6 of them (13.6%) - due to disease progression. Thus, the 12-year OS was 70.5%. 26 (59%) of 44 patients in LCP were alive by 12 years of therapy of TKI. 18 (41%) of 44 patients died, 15 of them (34.1%) - due to disease progression. 13 (50%) of 26 patients receiving imatinib in the 1-nd line therapy, 13 (50%) - TKI in the 2-nd line therapy: 5 (38.5%) patients receiving nilotinib, and 8 (61.5%) patients receiving dasatinib. Thus, the 12-year OS was 59%. Summary/Conclusion: Our study showed the high efficacy of TKI in the 1- nd and 2-nd lines therapy in non-selected patients with CML in routine practice. Disclosures No relevant conflicts of interest to declare.

Therapy with Lower Dose Dasatinib in Newly Diagnosed Early Chronic Phase-Chronic Myeloid Leukemia (CML-CP)

Therapy with Lower Dose Dasatinib in Newly Diagnosed Early Chronic Phase-Chronic Myeloid Leukemia (CML-CP)

The BCR-ABL1 transcript type influences response and outcome in Philadelphia chromosome-positive chronic myeloid leukemia patients treated frontline with imatinib.

The most frequent BCR-ABL1 fusion transcripts in chronic myeloid leukemia (CML) are the e13a2 (b2a2) and the e14a2 (b3a2) ones. In the imatinib era few studies addressing the prognostic significance of the BCR-ABL1 transcript type in early chronic phase CML have been published. Overall, these studies suggest that in e14a2 patients the response to imatinib is faster and deeper. To evaluate if the BCR-ABL1 transcript type (e13a2 compared to e14a2) affect the response to imatinib and the clinical outcome in newly diagnosed adult CML patients, 559 patients enrolled in 3 prospective studies (NCT00514488, NCT00510926, observational study CML/023) were analyzed. A qualitative PCR was performed at baseline: 52% patients had a e14a2 transcript, 37% a e13a2 transcript, 11% co-expressed both transcripts and 1% had other rare transcripts. The median follow-up was 76 months (95% of the patients had at least a 5-year observation). The complete cytogenetic response rates were comparable in e14a2 and e13a2 patients. The median time to MR3.0 (6 and 12 months) and MR4.0 (41 and 61 months) was significantly shorter for e14a2 patients compared to e13a2 patients, with a higher cumulative probability of MR3.0 (88% and 83%, P < .001) and MR4.0 (67% and 52%, P = .001). The 7-year overall survival (90% and 83%, P = .017), progression-free survival (89% and 81%, P = .005) and failure-free survival (71% and 54%, P < .001) were significantly better in patients with e14a2 transcript. In conclusion, patients with e13a2 transcript had a slower molecular response with inferior response rates to imatinib and a poorer long-term outcome.

Brief Research Report: Novel Compound BCR-ABL Mutations in Late Chronic Phase Imatinib Sensitive CML Patients Are Associated with Progression to Advance Disease Phase

Introduction: BCR-ABL kinase domain (KD) mutations have well established role in tyrosine kinase inhibitors (TKIs) resistance and disease progression in chronic myeloid leukemia (CML)1. In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib2. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib sensitive CML patients3. Furthermore, BCR-ABL mutation detection is currently recommended only in case of drug resistance and disease progression and clinical significance of BCR-ABL mutation detection in TKI responder chronic phase CML is not well documented4. Therefore, we investigated presence of ABL-KD mutations in chronic phase (CP) and advanced phase imatinib sensitive CML to find out association of BCR-ABL mutations with progression to advanced disease phases in CML patients. .Patients and Methods: Imatinib sensitive CML patients in CP and advanced phases of the disease were included in the study.All CP patients were incomplete hematological, complete cytogenetic and major molecular responses. Due to specific study objectives, patients manifesting drug resistance during follow-up studies were excluded from the study. A total of 90 imatinib sensitive CML patients (CP=41, late CP=33, and accelerated phase=16) were finally available for analysis. All patients as well as 10 healthy controls were investigated for BCR-ABL mutations using Sanger sequencing. All response criteria were per European LeukemiaNet guidelines4. Data was analyzed using SPSS software (version 19).Results: Mean age of the patients was 33 years (Table 1). Eleven out of 33 (33.3%) patients in late-CP CML harbored 24 types of point mutations, out of which eight (72.72%) harbored compound mutated sites (Figure 1, Table 2). E355G (3.33%) was the most prevalent mutant. Five patients (45.45%), all of which had compound mutations, progressed to advanced phases of disease during follow up studies. No BCR-ABL mutation was detected in healthy subjects and in early CP CML patients. Therefore, early CP CML patients served as additional control in this study. BCR-ABL mutations were found in 3 accelerated phase patients as well. Late-CP mutations were associated with elevated platelet count (p= 0.037) and male gender (p= 0.049). The median overall survival and event free survival of CML patients (n=90) was 6.98 and 5.8 years respectively. Seven year survival was found to be 94.2%.Discussion and conclusions: Compound BCR-ABL mutations were associated with progression to advanced disease in imatinib sensitive late-CP CML patients. Although single BCR-ABL mutations have previously been found to cause CML progression5, this is first report of association of compound BCR-ABL mutations with disease progression in stable imatinib responders at late CP. Detection of new mutations can help in defining mechanism of CML progression6. Moreover, BCR-ABL mutation detection in late CP CML patients sensitive to TKI treatment can help in early assessment of risk for disease progression and/or drug resistance and subsequent clinical intervention to delay disease progression which is a major challenge of CML therapy in TKI era7.

Deep Molecular Response to Nilotinib As First-Line Treatment of BCR-ABL+ CML in Early Chronic Phase: A Phase 3b Multicenter Study of the Gimema CML Working Party

Deep Molecular Response to Nilotinib As First-Line Treatment of BCR-ABL+ CML in Early Chronic Phase: A Phase 3b Multicenter Study of the Gimema CML Working Party

Inhibitory Effects of Icaritin on TKI-Resistant CML Cells through Disruption of the BCR-ABL-GRB2-RAS-MAPK Signaling Pathway

Abstract The ABL tyrosine kinase inhibitor (TKI) Imatinib Mesylate (IM) is effective at inducing clinical remission in early phase chronic myeloid leukemia (CML) patients, but is not curative. Early relapses and acquired drug resistance remain some issues in IM-treated patients. In particular, relapses are frequently associated with point mutations in the BCR-ABL tyrosine kinase domain (TK, &gt; 50%). Newer TKIs, dasatinib (DA) and nilotinib, have increased potency over IM and show a broader spectrum of activity against mutant forms of BCR-ABL. However, none of these agents is able to target a critical T315I gatekeeper mutation of BCR-ABL in TKI-resistant patients. We have demonstrated that CML stem cells are genetically unstable and generate many BCR-ABL TK mutations in vitro and in vivo. They are also less responsive to TKIs and are a critical target population for TKI-resistance. Thus improved treatment approaches to specifically target CML stem cells and BCR-ABL-T315I resistant cells are clearly needed. It has recently been reported that estrogen receptor variant ERα36 is highly deregulated not only in breast cancer cells, but also in liver cancer and leukemic cells, and that targeting this specific variant with a small molecular inhibitor (Icaritin, SNG162) inhibits CML cell growth. However, the underlying molecular mechanisms of these observations are not understood. Whether this inhibitor, alone or in combination with new ABL inhibitors, can target primary CML stem/progenitor cells and T315I-resistant cells have also not been investigated. In this study, we utilized two cell line model systems: K562 cells and IM-resistant K562 cells without BCR-ABL TK mutation and human UT7 cells expressing either wild type BCR-ABL or carrying the BCR-ABL-T315I mutation. We have now demonstrated that protein expression of ERα36 is highly upregulated in both IM-resistant and BCR-ABL-T315I mutant cells as compared to control cells. Interestingly, the use of pre-clinically validated ERα36 inhibitors (SNG162 and SNG1153) alone inhibits cell growth and induces apoptosis of these cells. BCR-ABL-T315I cells are more sensitive to ERα36 inhibitors treatment, with twofold increases in Annexin V+ cells detected in BCR-ABL-T315I cells after SNG1153 treatment, compared to those detected in BCR-ABL expressing cells. These effects can be further enhanced by combination treatment with a TKI. Importantly, we have discovered that treatment of IM-resistant and BCR-ABL-T315I mutant cells with SNG162 and SNG1153 inhibitors, alone or with a TKI, significantly reduced phosphorylation of BCR-ABL on tyrosine residue 177 (Tyr177), a residue essential for BCR-ABL induced leukemogenesis through its binding to GRB2 and activation of the downstream RAS-MAPK pathway. This new observation was supported by detection of a significant reduction in phosphorylation of MEK1/2 kinase, an important component of the RAS-MAPK pathway, in these cells. Most importantly, IP-Western analysis further demonstrated that the BCR-ABL-GRB2 protein interaction was markedly interrupted in cells treated with SNG inhibitors plus a TKI, which correlates with reduced phosphorylation of Tyr177 in these cells. Moreover, colony-forming cell (CFC) assays showed that SNG inhibitors (SNG162 and SNG1153) in combination with a TKI are more effective at inhibiting growth of CD34+ treatment-naïve IM-nonresponder cells as compared to single drug treatment (46% vs. 25%). We further demonstrated that SNG162 and SNG1153 (up to 10 μM and 5 uM) are not toxic to CD34+ normal bone marrow cells. Interestingly, a combination treatment of DA plus SNG1153 dramatically reduced the level of engrafted leukemic cells in transplanted immunodeficient NSG mice and prolonged the survival of these mice compared to mice treated with DA alone. Median survival of DA treated mice is 87.5 days, while some DA and SNG1153 treated mice remain alive for more than 102 days after transplantation. ERα36 thus emerges as an attractive druggable target for combination therapies to target TKI-insensitive CML stem/progenitor cells and T315I-resistant cells. Disclosures Zhang: Shenogen Pharma Group Ltd: Employment. Ding:Shenogen Pharma Group Ltd: Employment. Lin:Shenogen Pharma Group Ltd: Employment. Meng:Shenogen Pharma Group Ltd: Employment.

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.

The Hasford Score Correlates with the Long-Term Molecular Response to Imatinib Treatment for Chronic Myeloid Leukemia Patients and May be Useful for Differentiating Low and Intermediate Risk Patients: A Single Institution Experience

BACKGROUNDSince the beginning of the tyrosine-kinase inhibitor (TKI) era in the treatment of chronic myeloid leukemia (CML), there have been attempts to stratify patients for optimal management. An essential requirement for perfect stratification was the identification of factors capable of predicting long-term response [1]. The Sokal and Hasford scores were developed in the chemotherapy and interferon alfa eras, respectively [2]. The EUTOS score was found to predict probability of complete cytogenetic response (CCyR) within 18 months of Imatinib initiation and progression-free survival (PFS) for patients receiving Imatinib [3]. However, the usefulness of the EUTOS score in predicting survival and outcome in patients with early chronic phase CML treated with TKI was questioned [4]. The Hasford score failed to differentiate patients who achieved low and intermediate risk scores according to CCyR, MMR, and 5 years EFS [5] and in our study we found Hasford score correlated with the long-term molecular response. PATIENTS AND RESULTSWe analyzed a cohort of 88 patients (F/M:42/46, median age 51 (21-83)) receiving standard dose Imatinib treatment for first chronic phase of CML. As assessed by Hasford risk analysis, the group comprised 57 low risk and 31 intermediate risk patients. In the initial group of patients, there were 5 high risk patients who were excluded from the study. No additional chromosomal abnormalities were identified at diagnosis. All patients achieved complete cytogenetic response (CCyR) and major molecular response (MMR) at time points defined by the European Leukemia Net (ELN). Of these, 42 patients lost MMR in a median time of 47 months. Within this group we identified 20 low risk (LR) and 22 intermediate risk (IR) patients. There was a significant difference in maintenance of the MMR between IR and LR patients (p=0.03, Figure 1). This analysis revealed that all intermediate risk patients lost MMR after approximately 85 months of Imatinib treatment, while 62% of the low risk patients maintained MMR throughout this time frame. During analysis, all 42 patients were switched to second generation TKI. After 3 months of second generation TKI treatment, median bcr-abl transcript levels in the LR group were 0.01 (0.000-0.295) but in the IR group bcr-abl levels were 0.301 (0.000-44.5) (p=0.0006, Figure 2). CONCLUSIONSAs the Hasford metric was designed for assessing patients treated with interferon alpha, we found our results to be interesting, and to be relevant to the discussion on optimizing scoring systems in chronic myeloid leukemia patients. If the observed difference between low and intermediate risk patients in maintaining MMR on Imatinib is confirmed, IR patients will become candidates for different first line treatment. Despite clinical studies, the choice between Imatinib and second generation TKI as the first line treatment remains an issue. Our results (if confirmed) promise to directly impact treatment decisions affecting IR patients.

ENESTnd Trial: A Phase III Study Comparing Nilotinib with Imatinib as Front-Line Therapy of Early Chronic-Phase Chronic Myeloid Leukemia

SUMMARY: The ENESTnd trial is a Phase III, randomized, open-label, multicenter trial, in which 846 patients with newly diagnosed chromosome Philadelphia-positive chronic-phase chronic myeloid leukemia were randomly assigned in a 1:1:1 ratio between three arms of treatment: imatinib mesylate 400 mg once daily, nilotinib 300 mg twice daily (b.i.d.), nilotinib 400 mg b.i.d. Nilotinib appeared superior to imatinib in terms of complete cytogenetic response at 12 months (77 vs 87 vs 85%; p &lt; 0.001); major molecular response at 12 months (primary end point; BCR–ABL1 on an International Scale &lt; 0.1%: 22 vs 44 vs 43%; p &lt; 0.001); deep response at 4 years (BCR–ABL1IS&lt; 0.0032%: 23 vs 40 vs 37%; p &lt; 0.0001). Less progression to advanced phases at 4 years (0.7 vs 1.1 vs 4.2% on core treatment) converted into a slight advantage in terms of overall survival at 4 years for the nilotinib 400 mg b.i.d. arm in Sokal intermediate- and high-risk patients. Tolerance and quality of life were in favor of nilotinib, with the noteworthy exception of cardiovascular events (1.5 vs 6.4vs 8.7% at 4 years). This trial led to the approval of nilotinib 300 mg b.i.d. as front-line therapy of chronic-phase chronic myeloid leukemia in 2010.

Nilotinib 300 mg BID as frontline treatment of CML: Prospective analysis of the Xpert BCR-ABL Monitor system and significance of 3-month molecular response

Sixty patients with early chronic phase CML (ECPCML) received Nilotinib on a phase II study which included a comparison of the Xpert BCR-ABL Monitor™ PCR system with standardized (IS) BCR-ABL1 real-time quantitative PCR (RQ-PCR). 88% patients achieved MMR with 45% achieving MR4.5. At 3 months BCR-ABL1/ABL1 IS >1% and <10% was associated with a lower likelihood of subsequent MR4.5 compared to patients with lower levels (p = 0.018). No significant difference was observed between methodologies in identifying MMR. Nilotinib induces high molecular response rates in ECPCML and the Xpert BCR-ABL Monitor™ system merits further investigation in this setting.

The e13a2 BCR-ABL1 Fusion Transcript Is a Candidate Adverse Prognostic Factor In Chronic Myeloid Leukemia Patients Treated Frontline With Imatinib Mesylate

Background and aimsThe e13a2 and the e14a2 are the most frequent BCR-ABL1 transcripts in chronic myeloid leukemia (CML) patients. The aim of the present study was to assess the prognostic value of the e13a2 (b2a2) or the e14a2 (b3a2) fusion transcripts on the long-term outcome of early chronic phase (ECP) CML patients treated frontline with imatinib mesylate (IM). Few studies, mostly based on a small number of patients or with a relatively short observation, have been published, particularly in ECP setting. Due to partially conflicting data, the transcript type is not actually considered an established baseline prognostic factor. To our knowledge, this is the first long-term analysis conducted in the context of large prospective studies. MethodsA retrospective analysis of 3 GIMEMA CML WP prospective clinical studies (NCT00514488, NCT00510926, observational study CML/023) was performed. All the 559 enrolled patients were analyzed. A qualitative RT-PCR for BCR-ABL1 transcript was routinely performed at enrollment. Patients expressing rare transcripts or with both e13a2-e14a2 transcripts were excluded: 493 out of 559 patients were included, 203 (41%) with e13a2 transcript and 290 with e14a2 transcript (59%). Definitions. Major molecular response (MMR): BCR-ABL1IS ratio <0.1%. Deep molecular response (MR4.0): detectable disease ≤ 0.01% BCR-ABL1IS or undetectable disease with ≥10,000 ABL1 transcripts. Progression: transformation to accelerated or blastic phase. Failure: according to 2013 ELN recommendations. Event: failure or permanent discontinuation for any reasons. All the deaths, at any time and for any reasons, were included. ResultsThe median follow-up was 76 months; 95% of the patients had at least a 5-year observation. The 2 groups were comparable for demographic and hematologic characteristics, except for the proportion of male patients, that was higher in the e13a2 group (p = 0.05), and for the baseline percentages of eosinophils, that was lower in the e13a2 group (p = 0.009). The Sokal, Hasford and EUTOS risk score distributions and the proportion of patients with CCA in Ph+ cells were comparable. The complete cytogenetic response (CCyR) rate at 12 month was not significantly different (75% and 79% in e13a2 e14a2 patients, respectively, p=0.274), but the MMR rate at 18 months and the MR4.0 at 36 months were significantly lower in e13a2 patients (52% and 67%, p = 0.001; 20% and 30%, p = 0.013, respectively). As far as the rapidity of response, the time to MMR and the time to MR4 were significantly slower for patients with e13a2 transcript (12 and 6 months; 54 and 37 months, respectively), with an inferior overall estimated probability of MMR (85% and 92%, p < 0.001) and MR4 (57% and 71%, p = 0.002). The overall survival (83% and 86%, p = 0.023), the progression-free survival (81% and 86%, p = 0.007), the failure-free survival (54% and 71%, p < 0.001) and the event-free survival (46% and 61%, p = 0.003) were significantly lower in patients with e13a2 transcript (figure 1). In a multivariate analysis (Cox model), the transcript type retained its prognostic significance, when adjusted for other relevant variables. Analyzing separately the patients treated with IM 400 mg (n = 371; e13a2 and e14a2 transcript: 208 and 163 patients, respectively) or IM 800 mg (n = 122; e13a2 and e14a2 transcript: 82 and 40 patients, respectively), all the above mentioned response and outcome differences were confirmed, with one exception: in the high-dose IM group the overall survival probability was inferior for the e13a2 patients, but, probably due to the small number of patients, the difference was not statistically significant (83% and 86%, p = 0.268). [Display omitted] ConclusionsA long-term analysis in a large cohort of CML patients suggests that the e13a2 transcript is an adverse prognostic factor in ECP CML patients treated frontline with IM. An independent evaluation is required for confirmation. AcknowledgmentsUniversity of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures:Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:BMS, Novartis: Consultancy.

EUTOS Score Predicts Optimal Response To Imatinib According To The Revised ELN Recommendations Better Than Sokal Score: A Study From The “Gruppo Triveneto LMC”

IntroductionOne of the most significant novelty of the revised version of the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia (CML) patients is that an earlier achievement of complete cytogenetic response (CCyR), at 6 months, and major molecular response (MMR), at 12 months, is regarded as optimal. Moreover, the prognostic value of the depth of molecular response at three months (i.e. BCR-ABL/ABL ratio ≤10%) is recognized. We have previously reported that EUTOS score is able to predict long term outcome of imatinib therapy, and that high-risk patients had a non-statistically significant lower probability to achieve all the cytogenetic and molecular endpoints defined as optimal by 2009 ELN recommendations. Aims and MethodsWe retrospectively evaluated our cohort of CML patients treated with front-line standard dose imatinib to test the ability of EUTOS and Sokal scores to foresee 2013 ELN-defined optimal response to therapy. A total of 314 consecutive patients treated with imatinib 400 mg daily for early chronic phase CML were analysed. Median age at diagnosis was 57 years (range: 19-85 years). According to the Sokal score there were 133 (42%) low risk, 127 (40%) intermediate risk, 52 (17%) high risk and 2 (1%) unknown risk cases, respectively. The distribution according to the EUTOS score was: 289 patients (92%) in the low-risk and 25 (8%) in the high-risk group. Partial cytogenetic response (PCyR) and CCyR were defined as 1-35% and 0% Ph+ metaphases, respectively; major molecular response (MMR) was defined as BCR-ABL <0.1%IS. For the purposes of this analysis, and as suggested by the ELN experts, we divided patients into low and high risk also according to Sokal score, thus considering low and intermediate risk as one group. ResultsConsidering EUTOS score, at the 3 months timepoint we observed a significant higher rate of optimal molecular response (≤10%) in low risk (76%) compared to high risk (52%, p=0.03) patients, while there was a only trend for cytogenetic response (Ph+ ≤35%) (86% vs 75%, p=0.20). At 6 months, both cytogenetic (CCyR) and molecular (≤1%) optimal responses were higher in the low risk group: 76% vs 46% (p=0.003) and 67% vs 33% (p=0.004), respectively. At 12 months, 58% of low risk patients were in MMR, compared to 41% in the high risk group (p=0.20). Dividing patients according to Sokal score in two groups of intermediate-low (n=260) and high (n=52) risk, we found a significant difference in the rates of cytogenetic response both at 3 (88% vs 72%, p=0.03) and at 6 (79% vs 48%, p=0.0001) months, while no significant differences were seen in molecular response at 3 (76% vs 62% p=0.13), 6 (67% vs 50%, p=0.08) or 12 (56% vs 55%, p=1.00) months. ConclusionsOur results suggest that EUTOS score is able to predict optimal response to imatinib, in particular achievement of molecular response at 3 months, a marker of emerging importance in foreseeing long-term outcome, and of CCyR at 6 months, that has been associated with superior progression-free and overall survival. Sokal score predict sensibly cytogenetic responses, but seems less efficacious in identifying patients that will achieve optimal molecular endpoints.Table 1Eutos Low (n=289)Eutos High (n=25)PSokal Low+Int (n=260)Sokal High (n=52)P3-mo. CyRPh+ ≤35%175150.20160290.03Ph+ >35%2952311n.e. / n.d.85577123-mo. MR≤10% IS118110.03108210.13>10% IS37103413n.e. / n.d.1344118186-mo. CyRPh+ 0%179110.003169210.0001Ph+ ≥1%57134423n.e. / n.d.5314786-mo. MR<1% IS11870.004106180.08≥1% IS59145318n.e. / n.d.11241011612-mo. MR≤0.1% IS10870.2096181.00>0.1% IS77107515n.e. / n.d.10488919 Disclosures:No relevant conflicts of interest to declare.

Imatinib-Treated CML Patients With Discordant Response Between Cytogenetic and Molecular Tests At 3 and 6 Month Timepoints Have a Reduced Probability Of Subsequent Optimal Response: A Study From The “Gruppo Triveneto LMC”

IntroductionThe 2013 version of the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia (CML) patients defines as optimal response the achievement of at least a partial cytogenetic response (PCyR) and/or BCR-ABL <=10% at 3 months, and of a complete cytogenetic response (CCyR) and/or BCR-ABL<1% at 6 months. Obtaining less than PCyR (i.e. Ph+ 36-95%) and/or BCR-ABL >10% at 3 months, and less than CCyR and/or BCR-ABL 1-10% at 6 months are regarded as warning. Patiens with discordant response between cytogenetic and molecular tests (e.g. PCyR and BCR-ABL >10% at 3 months) may be alternatively considered at the same timepoint as optimal or warning. Aims and MethodsTo evaluate the outcome of CML patients with discordant results between cytogenetic and molecular tests, we retrospectively analyzed our cohort of early chronic phase CML patients for which both cytogenetic and molecular responses were evaluable at 3 and/or 6 months. All patients received front-line imatinib 400 mg daily. PCyR and CCyR were defined as 1-35% and 0% Ph+ metaphases, respectively; major molecular response (MMR) was defined as BCR-ABL <=0.1%IS. Failure-free survival (FFS) was measured from the start of imatinib to the date of any of the following events: progression to accelerated or blastic phase (ABP), death for any cause at any time, imatinib dose increase (>=600 mg/day) or switch to nilotinib/dasatinib for primary or secondary hematologic or cytogenetic resistance. Cumulative responses and survival probabilities were estimated by the Kaplan-Meier method and compared by log rank test; differences among variables were evaluated by the Fisher's exact test. ResultsA total of 201 patients were analyzed. Median age at diagnosis was 55 (range 20-84) years. The distribution according to the Sokal score was: 86 (42.8%), 79 (39.3%) and 36 (17.9%) patients for low, intermediate and high risk, respectively. We observed that patients with concordant optimal (n=110) and discordant (n=19) results at the 3 month timepoint had significantly different chances of subsequent 6-month CCyR (88% vs 40%, p<.0001) and 12-month MMR (68% vs 12%, p<.0001), while there were no significant differences between patients with discordant or concordant warning (n=21) results (6-month CCyR 40% vs 14% and 12-month MMR 12% vs 0%, respectively). Also, patients with discordant results, compared to concordant optimal patients, had a significantly longer median time to CCyR (10.5 vs 3.5 months, p<.0001) and to MMR (49.6 vs 9.1 months, p<.0001), while there were no differences between discordant and concordant warning patients. Similarly, considering the 6-month timepoint, patients with discordant (n=28) results had a significantly inferior probability of subsequent 12-month MMR compared to concordant optimal (n=104) patients (16% vs 82%, p<.0001) but not different from concordant warning (n=38) cases (7%). Long-term FFS was significantly different between concordant optimal, discordant and concordant warning patients both considering the 3-month (82.8% vs 52.7% vs 9.6%, respectively) and the 6-month (90.4% vs 67.9% vs 23.7%, respectively) timepoints (figure). ConclusionsOur results suggest that only CML patients with concordant cytogenetic and molecular optimal response at the earlier timepoints have an excellent probability of obtaining subsequent MMR and a favourable long-term FFS, while patients with at least one warning result should be carefully monitored, since their risk of treatment failure is higher. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors

Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.