Cumulative Incidence Of Major Molecular Response Research Articles

Treatment-Free Remission Era: BCR-ABL1 mRNA Transcript Level

Background: Early acquisition of a deeper molecular response (DMR) and maintenance of a sustained DMR are prerequisites for implementing treatment-free remission (TFR) in CML patients. Earlier identification of patients who have not reached 24-month DMR and timely intervention is particularly important for patients with a strong desire for TFR. Early molecular response (EMR) of BCR-ABL1 mRNA <10% at 3 months after the initiation of TKI therapy is strongly predictive of a 12-month major molecular response (MMR). Whether the EMR <10% is also a good predictor of the 24-month DMR is unknown. Exploring early predictors of 24-month DMR could help guide clinical treatment decisions and advance the implementation of the TFR plan. Aim: Exploring early predictors of 24-month DMR. Methods: We performed a retrospective analysis of all adult patients with newly diagnosed CML-CP in the Department of Hematology at Guangdong Provincial People's Hospital (Guangzhou, China) between Mar 2009 and May 2019. Patients were monitored with BCR-ABL1 mRNA quantitative RT-PCR monthly for the first 3 months of TKI treatment, then every 3 months for a minimum of 2 years, and then every 3 to 6 months. Results: A total of 314 patients with complete medical recorders and routinely monitoring BCR-ABL1 mRNA transcript data of each molecular response milestone were enrolled. Patients' characteristics are summarized in Table 1. The median follow-up time was 54 months (14 to 146 months). The 5-year cumulative rate of MMR, MR 4 and MR 4.5 with TKI treatment were 80%, 48.1%, and 38.4%, respectively. The results of the ROC analysis showed that a 3-month BCR-ABL1 mRNA transcript level of 4.94% correlated well with the 24-month DMR. The sensitivity and specificity of its predictive function were 82.8% (95% CI, 73.6-89.8) and 66.97% (95% CI, 60.3-73.1), respectively. So, we adopted BCR-ABL1 mRNA transcript level ≤4.94% at 3 months as the optimal threshold for predicting 24-month DMR. To reveal the cumulative incidence (CI) of 12-month MMR, 24-month MR 4 and MR 4.5 at different thresholds of BCR-ABL1 mRNA transcript levels at 3 months. Patients were divided into 3 groups according to the BCR-ABL1 mRNA transcript levels, group I <5% (n=150, 47.7%), group II 5% to 10% (n=36, 11.5%), group III >10% (n=128, 40.8%). Patients with BCR-ABL1 mRNA transcript levels <5% at 3 months after TKI initiation are more likely to achieve DMR than the other two groups and take less time to achieve DMR. Patients of Group I with 12-month MMR and 24-month MR 4 were significantly higher than the other two groups, with 66.7% vs 30.6% or 8.6% and 50% vs 16.1% or 7% (P<0.001), respectively. And group II was compared with group III. The cumulative incidence of MMR, MR 4 and MR 4.5 was also significantly higher in Group I than in the other two groups (Fig.1). The survival outcome of patients with BCR-ABL1 transcript levels <5% at 3 months had significantly superior compared with those with BCR-ABL1 transcript levels ≥5%: the 5-year EFS， PFS and OS were 88.6% vs 86.4% (P=0.037), 100% vs 95.7% (P=0.011) and 100% vs 95% (P=0.014)， respectively (Fig. 1). Conclusion: BCR-ABL1 mRNA transcript levels <5% at 3 months is a new landmark EMR (EMR <5%) which can predict 24-month DMR for patients with TKI treatment. EMR <5% may be used to guide the clinical timely switching of TKI or treatment and facilitate the implementation of TFR.

Lower-Initiating Dose of Bosutinib for Resistant or Intolerant to Prior Therapy Chronic Myeloid Leukemia Patients (BOGI trial): A Single-Arm, Multicenter, Phase II Trial

Introduction: The introduction of ABL1 tyrosine kinase inhibitors (TKIs) has markedly improved the survival outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Second-generation TKIs are highly active for patients with newly diagnosed and resistant/intolerant CML-CP. Although bosutinib is generally safe, drug-related toxicities (DRTs) such as diarrhea or increased transaminase leading to treatment discontinuation, are often observed. The standard initial daily dosage of bosutinib is 400 mg for newly diagnosed or 500 mg for resistant/intolerant patients with CML-CP, whereas some experts suggest lower dose (200-300 mg) initiation is recommended to reduce adverse events (AEs). However, the safety and efficacy of lower dose initiation of bosutinib are unknown. Hence, we conducted a phase 2 study of BOsutinib Gradual Increase as a second/third-line treatment for CML-CP (BOGI trial, UMIN 000032282) to clarify whether a lower initiating dose of bosutinib (200 mg daily) would reduce discontinuation or interruption of treatment due to DRTs. Patients and methods We included CML patients who developed at least one line of treatment failure (resistant or intolerant), aged >18 years with an ECOG performance status of 0-2 and adequate organ function. After enrollment, the patients initiated 200 mg of bosutinib daily; subsequently, dose escalation was performed by 100 mg daily (up to 500 mg daily) every 2 weeks if no grade 3 or higher AEs occurred. BCR::ABL1 mRNA levels were measured by the standardized international scale at a central laboratory at 3, 6, 9, and 12 month since treatment initiation. The primary endpoint was the treatment discontinuation rate due to DRTs at 12 months. Secondary endpoints included the treatment interruption rate, mean bosutinib dosage, dosing days and relative dose intensity until 12 months, achievement of cytogenetic response (CCyR), cumulative rates of major molecular response (MMR) or deep molecular response (DMR). Sample size calculation was performed by research and biostatistics SWOG statistical tools (at null proportion = 0.32, alternative proportion = 0.14, one-sided α error = 5% and β error = 20%, power 80%) with the discontinuation rate of the previous Japanese phase 1/2 study of bosutinib as a reference (Nakaseko C, et al. Int J Hematol. 2015). Considering protocol deviations, sample size was 35 participants. Results Between Feb 4, 2019, and May 24, 2022, 35 patients enrolled from four Japanese hospitals. The median age was 61 years (range, 26 - 81 years); 19 patients were male and 16 were female and 16, 12, and 7 patients had low,intermediate, and high Sokal scores, respectively. Ten patients had hypertension, five had diabetes millitus, three had chronic heart disease, two had solid tumor, and one had cerebrovascular disease, respectively. Numbers of patients with previous TKIs were one for 19 (54%), two for 12 (34%) and three for 4 (11%), respectively and prior TKIs are imatinib (8, 23%), dasatinib (27, 77%), nilotinib (16, 46%) and bosutinib (1, 3%), respectively. In the intention to treat population, the bosutinib discontinuation rate at 12 months was 25.7% (95% CI, 15.6-39.3%) which is significantly lower than that of the previous report (v.s. 43.0%, p=0.019). Similarly, bosutinib discontinuation rate due to DRTs was 11.4% (95% CI, 5.2 - 23.2%), which is also significantly lower (v.s. 32%, p = 0.005). These results suggest lower initiating dose of bosutinib reduced bosutinib discontinuation rate due to DRTs, thus the primary endpoint was met. A total of 22 patients (62.9%) interrupted bosutinib at least once. Median bosutinib dosage, bosutinib dosing days and relative dose intensity until 12 months were 391.7 (204.9-477.3) mg/day, 351.0 (20-365) days and 78% (41-95), respectively. 28 patients (80.0%) achieved cytogenetic response (CCyR) at 6 months; cumulative incidence of MMR and DMR at 12 months were 23 (65.7%; 95%CI, 49.2-79.2%) and 15 (42.9%; 95%CI, 28.0-59.1%), indicating these secondary endpoints were comparable with the previous report. Grade 3 to 4 transaminase elevation was 20% which is comparable with the previous report (v.s. 29%, p=0.427), while a lower rate of diarrhea (3%; v.s. 25%, p=0.009) was notable. Conclusion The lower initiating dose followed by a gradual dose increase of bosutinib reduced the drug discontinuation rate due to severe DRTs, especially diarrhea, while efficacy was assured.

Canadian real-world experience of asciminib treatment in heavily pre-treated chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy

BackgroundAsciminib is a novel drug specifically targeting ABL myristoyl pocket in the ABL1 protein. MethodsForty one patients with chronic myeloid leukemia treated with asciminib from 2018 to 2022 were reviewed and analyzed for the efficacy and tolerability of asciminib using real-world experience data. ResultsThe median age was 60 years (range 17–90) with a past history of a cardiovascular event in 21 patients (51%). Patients were pretreated with a median of 3 previous tyrosine kinase inhibitors (range 1–5). After a median of 12 months of asciminib (range 3–41), major molecular response (MMR) rate was 39% (n = 11/28) and 42% (n = 5/12) at 6 and 12 months, respectively. Molecular response with 2 log reduction (MR2) was noted in 54% (n = 15/28) and 50% (n = 6/12) at 6 and 12 months. The cumulative incidence of MMR and MR2 was 46.3% and 66% at 12 months.Five patients discontinued asciminib due to treatment failure (n = 3) or thrombocytopenia (n = 2). There were no cardiovascular events. Out of 7 patients treated with high dose asciminib for T315I mutation, 5 patients achieved MMR or deeper response. The event-free survival was 63% at 12 months. ConclusionThis study confirmed clinical efficacy and tolerability of asciminib with real-world experience.

Two-Year Updated Results of Asciminib Managed-Access Program (MAP) in Russia

Background: Asciminib is a Specifically Targeting the ABL Myristoyl Pocket (STAMP) ABL. kinase inhibitor that has shown efficacy and a good safety profile in clinical trials in patients with Ph-positive chronic myeloid leukemia (CML) failing prior TKI lines. It was confirmed by real world data in Novartis approved Managed Access Program (MAP) in several countries.Aim: to present two-year updated results of asciminib use in clinical practice in the MAP program in 3 centers of Russia. Methods: In total the data of 50 CML pts who received asciminib for more than 9 months and did not undergo bone marrow transplantation was analyzed. Pts recruitment, dosing regimen, response monitoring, and toxicity control were performed according to the MAP treatment plan. All pts had a chronic phase (CP) CML, 8 pts had a second CP after accelerated phase (n=7) or blast crisis (BC). Complete cytogenetic response (CCyR) corresponding to BCR::ABL1 ≤1%, major molecular response (MMR) and deep molecular response (MR4) achievement was assessed by cumulative incidence function (CIF) with Gray's test for comparison responses in subgroups. Survival analysis was performed by Kaplan-Meier method. Results: All pts were divided into two groups: 20 pts received an initial dose of 200 mg BID (19/20 pts with BCR::ABL1 T315I ), 30 pts received 40 mg BID (1/30 pts with BCR::ABL1 T315I ). Baseline characteristics of the two dose groups are presented in table 1. The median follow-up among all pts was 17 months (range 10-37); 7(14%) pts discontinued asciminib (5 due to resistance, 2 due to progression). Two-year survival rate without treatment discontinuation was 83%. The 2-year OS was 100% and 93% in 400 mg and 80 mg dose groups, respectively, two (4%) pts progressed to BC and died. CIF of CCyR, MMR and MR4 by 24 month was 55%, 29% and 17% for 80 mg dose and 45%, 48% and 45% for 400 mg dose respectively. There was no significant difference in response rates between the two dose groups. In the 400 mg dose group, the cumulative incidence of MMR was significantly higher in ponatinib-naive patients (75% vs. 23% in ponatinib-pretreated patients, p=0.006) (figure 1). Twenty two (44%) pts experienced any adverse events (AEs) and 8 (16%) had AEs of grade 3-4. AEs of grade 3-4 connected with asciminib included neutropenia, thrombocytopenia and irregular menstruation. No pts stopped treatment due to toxicity; no difference in toxicity was found between doses of 80 and 400 mg/day. Conclusion: Asciminib shows promising results for the treatment of highly pre-treated CML pts and should be considered as therapeutic options for pts with failure to previous TKIs. The 400 mg dose was well tolerated and highly effective in ponatinib-naive pts with BCR::ABL1 T315I and should be investigated in clinical trials in patients without T315I as a potentially more effective and well tolerated dose. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Long-term outcome of tyrosine kinase inhibitor treatment in children and adolescents with newly diagnosed chronic myeloid leukemia in chronic phase.

Long-term outcome of tyrosine kinase inhibitor treatment in children and adolescents with newly diagnosed chronic myeloid leukemia in chronic phase.

The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia.

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]

Sex and Major Molecular Response to Imatinib Treatment for Patients with Chronic Myeloid Leukemia

Objective: The prognosis for chronic myeloid leukemia (CML) has been significantly improved in the era of tyrosine kinase inhibitors (TKIs) whose leader is Imatinib mesylate (IM). Obtaining a major molecular response (MMR) is a major objective to achieve. However, the difference in response between the two sexes is often controversial. This work aims to evaluate the molecular response according to sex in Algerian patients with chronic phase CML (CML-CP) treated with IM in first intention. Methods: All Novo CML patients benefited from molecular follow-up by quantification of transcripts by real-time quantitative PCR (RQ-PCR). The cumulative incidence of MMR (CIMMR) was estimated by the Kaplan-Meier method. The comparison was made using the parametric Log-Rank test. A value of P ≤ 0.05 is considered significant. Results: Fifty-five patients were included in this study, with a mean age of 45.7 ± 13.9 including 29 men (53%) and 26 women (47%). For women, the incidence of Mb3a2 transcript was higher than that of Mb2a2 (72% vs. 28%, P=0.12). Men, on the other hand, had an almost equal distribution (52% vs. 48%, P = 0.88). The CIMMR for men was lower than that for women (45% vs. 80%, P=0.018). Conclusion: Women seem to respond more favorably to IM than men.

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

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

Results of following up patients with chronic myeloid leukemia and a deep molecular response without tyrosine kinase inhibitor therapy

To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy. The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year's duration were adverse events, pregnancy, and patients' decision. Information was collected retrospectively and prospectively in 2008-2016. The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p ≤ 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss. Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied.

High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients

Pharmacogenetic studies in chronic myelogenous leukemia (CML) typically use a candidate gene approach. In an alternative strategy, we analyzed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using a DNA chip containing 857 SNPs covering 94 drug transporter genes. Two cohorts of CML patients treated with imatinib were evaluated: an exploratory cohort including 105 patients treated at 400 mg/d and a validation cohort including patients sampled from the 400 mg/d and 600 mg/d arms of the prospective SPIRIT trial (n=239). Twelve SNPs discriminating patients according to cumulative incidence of major molecular response (CI-MMR) were identified within the exploratory cohort. Three of them, all located within the ABCG2 gene, were validated in patients included in the 400 mg/d arm of the SPIRIT trial. We identified an ABCG2 haplotype (define as G-G, rs12505410 and rs2725252) as associated with significantly higher CI-MMR in patients treated at 400 mg/d. Interestingly, we found that patients carrying this ABCG2 "favorable" haplotype in the 400 mg arm reached similar CI-MMR rates that patients randomized in the imatinib 600 mg/d arm. Our results suggest that response to imatinib may be influenced by constitutive haplotypes in drug transporter genes. Lower response rates associated with "non- favorable" ABCG2 haplotypes may be overcome by increasing the imatinib daily dose up to 600 mg/d.

Pharmacologic Monitoring of Dasatinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP-CML) Identifies Patients At Higher Risk of Pleural Effusion: A Sub-Analysis of the OPTIM-Dasatinib Trial

AbstractAbstract ▪3770▪This icon denotes a clinically relevant abstract Background:Second generation tyrosine kinase inhibitors such as dasatinib (Sprycel®, Bristol-Myers Squibb) induce significantly higher levels of cytogenetic and molecular responses than imatinib when given as frontline therapy for chronic phase chronic myelogenous leukemia (CP-CML) (DASISION trial, Kantarjian et al., NEJM 2010). Dasatinib is associated with the occurrence of pleural effusions (PE). The cumulative incidence of all grades PE in DASISION trial was reported to be 10% by 12 months and 14% by 24 months. Aims:To analyse efficacy of dasatinib first line and to test risk factors associated with the occurrence of PE. (EudraCT 2008–006854–17). Methods:Newly diagnosed CP-CML patients (pts) were assigned to dasatinib 100 mg/d. Dasatinib Cmin levels were assessed 24+/−2h after intake by tandem mass spectrometry after 2 weeks of therapy and every 3 months during 12 months thereafter. Pts with high Cmin values (Cmin ≥ 3 nM) at day 15 were randomized between dasatinib dose reduction or not. As the trial is still recruiting, the effect of randomization (treatment adaptation) was not analysed. For the purpose of this study, patients with at least 12 months follow-up were analysed for efficacy and all enrolled patients were analysed for safety. Molecular assessments were expressed as BCR-ABL/ABL (IS) in %. Results:Efficacy. In March 2012, 125 pts out of 191 pts enrolled in the trial had at least 12 months follow-up. Sokal scores were high for 18%, intermediate for 36% and low for 46% of pts. The median age was 52 (18–89) years. The rates of complete cytogenetic responses (CCyR) at 3, 6, and 12 months were 74%, 87%, and 97% respectively on evaluable samples, and 60%, 82%, and 95% when results were analysed according to the intention-to-treat principle taking into account missing values. The cumulative incidences of major molecular response (MMR) by 3, 6, 9 and 12 months were 21%, 46%, 56%, and 62% respectively. Of note 11 pts (9%) did not have a BCR-ABL (IS) ≤10% at 3 months. None of these patients reached a MMR by 12 months compared to a 68% (95% CI: 60–77) cumulative incidence of MMR in the other 114 pts. At 12 months, molecular response 4.5 (MR4.5) rate was 25%, including 80% of the pts with undetectable BCR-ABL transcript (sensitivity 4 to 5 log). Safety. 12 pts out of 191 (6.3%) presented a PE corresponding to a cumulative incidence of 9% by 24 months. 95 pts had at least one high Cmin value during the pharmacokinetic follow-up and 10 pts developed PE as compared to 2 out of the 96 remaining pts (p= 0.018). Cumulative incidence of PE by 24 months was 13.4% in high Cmin group as compared to 4.8% in low Cmin group (p=0.04). We next analysed whether the measurement of dasatinib Cmin at day 15 could predict the risk to develop a PE. Fifty pts (26%) had a high Cmin value at day 15 (group A) and 141 had a low Cmin (group B). The cumulative incidence of PE by 24 months was 17.4% in group A compared to 6.9% in group B (p=0.021) (fig 1). We next search for clinical factors influencing Cmin value at day15 of dasatinib 100 mg/d. Median Cmin values were significantly higher in patients aged 50 and over as compared to younger patients (2.5 nM versus 1.6 nM, p=0.0032). As expected, age 50 and over was also associated with an increased risk of pleural effusion. Conclusion:Current data demonstrate efficacy of dasatinib 100 mg/d similar or even better to that reported in other frontline trials such as the DASISION trial. We provide evidences suggesting that a high Cmin (>3nM) at day 15 and/or age 50 and over identify patients treated with dasatinib 100 mg/d with a high risk of PE. The benefit of dasatinib dose reduction is randomly tested for this group of patients in the OPTIM-Dasatinib trial and may be a major issue in elderly patients. [Display omitted] Disclosures:Rousselot:BMS, Novartis: Research Funding. Nicolini:BMS, Novartis: Consultancy, Research Funding. Coiteux:Novartis, BMS: Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Roy:Novartis, BMS: Speakers Bureau. Dartigeas:Roche: Consultancy. Guilhot:ARIAD: Honoraria. Mahon:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy.

BCR-ABL Fusion Transcript Do Not Significantly Influence the Outcome of Chronic Myeloid Leukemia Patients In Early Chronic Phase Treated with Imatinib Mesylate: a GIMEMA CML WP Analysis.

AbstractAbstract 1230 Background:Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL fusion gene. Different types of BCR-ABL transcripts can be found, due to different genomic breakpoints and alternative splicing. The most frequent transcripts are the e13a2 (b2a2) and the e14a2 (b3a2), that codify for a p210 protein. Occasionally, both transcripts may be present. In the imatinib (IM) era, few data about the prognostic significance of the transcript type are available, particularly in the setting of early chronic phase (ECP): one study suggested that patients with the b2a2 transcript may be more sensitive to IM (de Lemos et al. Genet Mol Res 2005), while two larger studies suggested that patients with b3a2 transcript may have better responses to IM (Vega-Ruiz et al. ASH 2007; Lucas et al. Haematologica 2009). No systematic evaluations in the context of large prospective clinical trials have been performed. AIM: To investigate the influence of the type of BCR-ABL fusion transcript on the responses and the outcome of CML patients treated with IM in ECP. Methods:We performed an analysis of 3 concurrent clinical trials of the GIMEMA CML Working Party (Clin Trials Gov. NCT00514488, NCT00510926 and the observational trial CML/023). Response monitoring was based on conventional cytogenetic examination (bone marrow) and quantitative molecular (Q-PCR) evaluation (peripheral blood). Definitions: Complete Cytogenetic Response (CCgR): 0% Ph+; Major Molecular Response (MMR): BCR-ABL/ABL ratio <0.1% (International Scale); failures: according to the revised European LeukemiaNet criteria (Baccarani et al. J Clin Oncol 2009). Results:559 consecutive CML patients in early CP have been enrolled from January, 2004 to January, 2007. Patients expressing rare transcript types (e1a2 and e19a2) and patients with the presence of both b2a2 and b3a2 transcripts were excluded: 493 out of 559 patients were evaluable, 203 (41%) with a b2a2 transcript and 290 with a b3a2 transcript (59%). The 2 groups were comparable (no significant difference in sex, age, Sokal and Hasford scores, clonal chromosomal abnormalities in Ph+ cells before IM and imatinib dose). The median observation time is currently 60 (extremes 2–80) months. In patients with b2a2 and b3a2 transcript, the observed 12-months CCgR rates were 77% and 80%, respectively; the cumulative incidence of CCgR was 89% and 88%, respectively (no significant differences). The time to MMR was significantly shorter for patients with b3a2 transcript (fig.1), but the cumulative incidence of MMR was not significantly different (81% and 86% in patients with b2a2 and b3a2 transcript, respectively). The probabilities of Failure-Free Survival, Progression-Free Survival and Overall Survival were 69% and 75%, 83% and 89%, 87% and 92% in patients with b2a2 and b3a2 transcript, respectively (fig. 1); no difference was statistically significant. Conclusions:In our experience, based on 493 early CP CML patients treated frontline with IM, the type of BCR-ABL fusion transcript had no relevant prognostic impact and no outcome differences have been observed so far. Acknowledgments:Work supported by European LeukemiaNet, COFIN, University of Bologna and BolognAIL. [Display omitted] Disclosures:Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta:Novartis: Honoraria. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Saglio:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baccarani:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.