Chronic Myeloid Leukemia In Chronic Phase Pts Research Articles

The Impact of EUTOS Long-Term Survival (ELTS) Score on Predicting Progression and Survival Among Turkish Patients with Chronic Myeloid Leukemia

Introduction and Objectives: For patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), four baseline prognostic scores are commonly used including the Sokal score and the most recently introduced EUTOS long-term survival (ELTS) score. The ELTS score was shown to be superior to the Sokal score for predicting survival. The aim of the study is to evaluate the value of ELTS score on predicting disease progression and survival in Turkish pts with CML-CP.Material and Method: Demographic, laboratory and clinical features, disease responses to tyrosine kinase inhibitor (TKI) therapy and survival of CML-CP pts, who received upfront imatinib (IM) between 2003 and 2018 were analyzed retrospectively. Treatment responses were reevaluated according to European LeukemiaNet 2013 recommendations. Risk groups analysis, discrimination and hazard ratios (HRs) were evaluated with Cox regression and Kaplan-Meier survival analysis. Receiver operating characteristic (ROC) analysis was performed to examine the effects of scores on predicting overall survival (OS) and progression-free survival (PFS).Results: A total of 185 pts were included, of which 103 (55.7%) were male and median age was 47 years (range, 16 - 81 years) (Table 1). The percentages of pts with low-, intermediate-, and high-risk ELTS scores were 60.5%, 25.9%, and 13.5%, respectively. For the Sokal score, these percentages were 37.3%, 40.5%, and 22.2% respectively. For Sokal high-risk pts, only 46.3% were classified as high-risk according to the ELTS score. Similarly, 44% of pts with intermediate Sokal risk had low-risk ELTS score (Fig. 1). Seventy-seven pts (41.6%) had at least one comorbidity, and the most common comorbidities were hypertension (21.6%), diabetes mellitus (13%), and ischemic heart disease (12.4%) (Table 1). The median durations of IM therapy and follow-up were 2728 (range, 14 - 6320 days) and 3473 (range, 71 - 6320 days) days, respectively. Complete hematologic and early molecular (BCR-ABL1 IS <10% at 3 months) responses at 3 months were 95.6% and 75.9%, respectively. Complete cytogenetic and major molecular response rates at 6 and 12 months were 72.3% and 86.1% and 45.4% and 54%, respectively. Thirty-five pts (18.9%) switched to second-generation TKI therapy and 6 pts (3.2%) progressed to advanced-phase disease during the follow-up (Table 1). For PFS, with reference to the low-risk Sokal score, the HR of high-risk groups was 9.301 (95% CI: 1.086-79.656, p=0.042) (Fig. 2A). Similarly, with reference to the low-risk ELTS score, the HR of intermediate- and high-risk groups were 4.744 (95% CI: 0.43-52.314, p=0.204) and 14.642 (95% CI: 1.523-140.791, p=0.020) (Fig. 2B). Regarding OS, with reference to the low-risk Sokal score, the HR of the intermediate- and high-risk groups were 1.835 (95% CI: 0.564-5.964, p=0.313) and 6.412 (95% CI: 2.11-19.489, p=0.001), respectively (Fig. 2C). With reference to the low-risk ELTS score, the HR of the intermediate- and high-risk groups were, 3.263 (95% CI: 1.242-8.576, p=0.016) and 7.258 (95% CI: 2.762-19.074, p<0.001) respectively (Fig. 2D). In the ROC analysis, the ELTS score was superior than the Sokal risk score for both predicting PFS (AUC=0.820 vs. AUC=0.818) and OS (AUC=0.762 vs. AUC=0.744). During the follow-up, 27 (14.6%) pts died, of which 6 died due to CML progression and causes of death were unrelated to CML in 21.Conclusion: In our study, we showed that the ELTS score could successfully predict high-risk pts compatible with the literature. With higher hazard ratios and better risk group stratifications, the ELTS score outperformed the Sokal score. The ELTS score can help clinicians to better discriminate poor prognostic pts and can promote optimal treatment strategies for these pts with potentially worse prognosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

An e13a2 Type of BCR-ABL Transcript Has a Significant Adverse Impact on the Achievement of a Sustained Deep Molecular Response and on the Maintenance of a Treatment Free Remission after Stopping Tyrosine Kinase Inhibitors

An e13a2 Type of BCR-ABL Transcript Has a Significant Adverse Impact on the Achievement of a Sustained Deep Molecular Response and on the Maintenance of a Treatment Free Remission after Stopping Tyrosine Kinase Inhibitors

Discontinuation of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia in chronic phase (CML-CP) in US clinical practice after guideline updates.

7548 Background: NCCN CML practice guidelines were updated in 11/2016 and in 9/2019 to include considerations for discontinuation of TKI therapy in patients (pts) with CML-CP. This study characterized TKI discontinuation practices in the US after these updates and drew parallels with a similar study conducted prior to these guideline updates (Ritchie et al. Leuk Lymphoma. 2019). Methods: Pt charts of adult CML-CP pts with TKI discontinuation (1/2017-12/2018) outside a clinical trial after achieving an adequate response were abstracted (11/2019-12/2019) via an online case report form by US oncologists/hematologists. Physicians’ assessment of adequate response (TKI duration, molecular response [MR], MR duration) and relapse were described. Results: 61 physicians (academic: 43%; community-based practices: 57%) contributed 153 pt charts. Most physicians were from large practices (57%), had &gt; 10 years (y) experience since completing subspecialty training (59%), and treated a median of 30 CML pts in the last 2y; 56% did not have access to precise molecular response monitoring for BCR-ABL of ≥4.5 log when attempting TKI discontinuation. Pts with TKI discontinuation had mean age 56 years, were mostly male (60%), white (69%), and had TKI discontinued in first-line (96%). Most common reasons for TKI discontinuation were pt request (54%) and adverse events (18%), besides achieving an adequate response. Physicians’ assessment of adequate response for TKI discontinuation are reported in the Table. 21% of pts (academic: 12%; community: 30%) relapsed after TKI discontinuation (treatment-free remission [TFR] failure; 66% relapsed within 1y). Conclusions: Although NCCN CML practice guidelines provide guidance for discontinuation of TKI therapy, there remains heterogeneity in US practice and TKI discontinuation is predominantly attempted in first-line (similar to Ritchie et al. 2019). TKI discontinuation is being practiced without adequate sensitive tools mandated by practice guidelines to monitor response. Broader application of practice guidelines for optimal TKI therapy discontinuation in CML-CP pts is needed, particularly in community-based practices, to improve long-term TFR rates. [Table: see text]

Treatment-free remission (TFR) following frontline (1L) nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 192-week data from the ENESTfreedom study.

7013 Background: In ENESTfreedom (NCT01784068), which evaluated TFR following 1L NIL in CML-CP pts, 51.6% remained in TFR 48 wks after stopping treatment (primary endpoint) and durability of TFR was demonstrated at 144 wks. Data from longer follow-up (192 wks) evaluating maintenance of TFR are reported. Methods: Pts with MR4.5 ( BCR-ABL1IS ≤0.0032%) and ≥2y of 1L NIL entered a 1y consolidation; pts with sustained deep molecular response (MR) were eligible for TFR. NIL was resumed after loss of major MR (MMR; BCR-ABL1IS ≤0.1%). At the latest data cut-off (Sep 17 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 190 pts entering TFR, 87 were ongoing, 91 had resumed NIL, and 12 had permanently discontinued. The TFR rate at 192 wks was 44.2% (84/190, 95% CI: 37.0–51.6%). Of 89 pts with successful TFR at 144 wks, 5 were not assessable for TFR at 192 wks as 2 had discontinued by 192 wks due to pt/physician decision, and 3 with MR4.5 previously did not have 192 wk PCR data. Of 91 pts who resumed NIL, 90 (98.9%) regained MMR and 84 (92.3%) regained MR4.5. 75/90 and 73/84 pts, respectively, had stable MMR and MR4.5 at 48 wks later. There were no cases of disease progression or new deaths. 10 deaths were reported in the 144-wk analysis, none due to CML. The 192-wk treatment-free survival rate was 48.7% (95% CI 41.4–55.6%). Of 89 pts remaining in TFR for &gt; 144 wks (including 87 pts for &gt; 192 wks), all-grade AE rates during consolidation and each subsequent 48 wk period of TFR were 84.3%, 77.5%, 70.8%, 48.3%, and 52.8%, respectively. All-grade musculoskeletal pain AE rates were 15.7%, 40.4%, 9.0%, 3.4% and 3.4%, respectively; cardiovascular event rates were low across these periods. Among pts who resumed NIL, most common AEs were nasopharyngitis (18.7%) and pruritus, fatigue, and increased lipase (14.3% each); the majority of AEs were grade 1/2. Conclusions: Results continue to support the long-term durability and safety of TFR at 192 wks after stopping 1L NIL; overall AE rates declined during the TFR phase and musculoskeletal pain AEs were transient. Pts should continue to be regularly monitored during TFR. Clinical trial information: NCT01784068.

Updated 18-Month Results from Dasfree: A Study Evaluating Dasatinib Discontinuation in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)

Updated 18-Month Results from Dasfree: A Study Evaluating Dasatinib Discontinuation in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)

Long-term treatment-free remission (TFR) following frontline (1L) nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom 144-wk results.

7063Background: ENESTfreedom (NCT01784068) is a phase 2 study evaluating TFR following 1L nilotinib in newly diagnosed CML-CP pts. We previously reported 48- and 96-wk TFR rates of 51.6% and 48.9%....

Phase II trial of dasatinib (DAS) in pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP).

10511 Background: Safe and effective treatment options for newly diagnosed (ND) or imatinib (IM) resistant/intolerant (R/I) pediatric CML pts are limited, and a large prospective study is needed. DAS has proven safety and efficacy in adults with ND or IM-R/I CML and is now being evaluated in a phase II trial of pediatric pts. Methods: CA180-226/NCT00777036 is an open-label nonrandomized prospective study of pts aged &lt;18 y in 3 cohorts: (1) CML-CP R/I to IM treated with DAS tablets 60 mg/m2 QD, (2) IM-R/I CML-AP/BP or Ph+ ALL (enrollment closed early due to poor response), and (3) ND CML-CP treated with DAS tablets 60 mg/m2 or DAS 72 mg/m2powder for oral suspension (PFOS) QD. Primary objectives were major cytogenetic response (MCyR) for CML-CP R/I to IM and complete cytogenetic response (CCyR) for ND CML-CP (MCyR &gt;30% and CCyR &gt;55% considered of clinical interest). Results: 113 pediatric CML-CP pts were treated. Cumulative rate of MCyR &gt;30% was reached as early as 3 mo (55%; [95% CI 36, 74]) for IM-R/I CML-CP. Cumulative rate of CCyR &gt;55% was reached as early as 6 mo (64% [95% CI 53, 74] for ND CML-CP; 61% [95% CI 46, 74] for pts on tablets and 70% [95% CI 51, 84] for pts on PFOS). Estimated PFS by 48 mo was &gt;75% for CML-CP R/I to IM and &gt;90% for ND CML-CP. One CML-CP pt R/I to IM died 1 y after stopping DAS from gastrointestinal bleeding. AEs were consistent with those observed in adults, except no DAS-related pleural/pericardial effusion or pulmonary arterial hypertension (PAH) were reported here. Conclusions: In the largest prospective trial of pediatric pts with CML-CP, target responses were met early and increased over time with DAS treatment. The efficacy and safety of DAS were consistent with previous reports in adults, except no cases of pleural/pericardial effusion or PAH were observed. These results suggest DAS is safe and highly effective in the first- or second-line treatment of pediatric CML-CP. Clinical trial information: NCT00777036. [Table: see text]

Early molecular response in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with dasatinib (DAS) or imatinib (IM) from DASISION.

7055Background: An exploratory landmark analysis from DASISION demonstrated improved PFS and OS in newly diagnosed CML-CP pts treated with DAS or IM who achieved BCR-ABL1 ≤ 10% at 3 mo, a milestone...

Impact of Ph+ Stem Cell Burden on Clinical Findings and Molecular Responses to First-Line Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia: The Results from the Interim Analysis of N-Road, Multi-Center a Phase II Study

Background: Second generation tyrosine kinase inhibitors (2G-TKIs) are more potent than imatinib against chronic myeloid leukemia in chronic phase (CML-CP) as a first-line therapy, and the majority of patients (pts) on 2G-TKIs could achieve favorable molecular responces over MR3.0 by 24 M (Saglio G, et al. Blood 2011, Kantarjian HM, et al. Blood 2012). It is also likey that molecular response at 3 M will predict outcome for CML-CP pts on imatinib. Furthermore, Mustjoki S, et al. showed that Ph+ stem cell burden at diagnosis is a prognostic marker of molecular responses at 3-9 M on dasatinib or imatinib (Leukemia 2013). Thus, early prognostic marker of outcome is feasible for CML-CP on TKIs.Methods: We are conducting a phase II study (N-road) for newly diagnosed CML-CP pts, in which nilotinib 300mg BID is given for 24 M and is to be escalated to 400mg BID if no optimal response at any check points. The primary endpoint is CMR rate by 24 M, and secondary endpoints include MR3.0/MR4.0 by 12 M and exploring prognostic factors. In this setting, the impact of initial Ph+ stem cell burden on clinical findings and therapeutic responses has been investigated in a sub-study. By July 2014, 48 pts were enrolled and BM CD34+ cell fractions could be evaluated by FACS-FISH analysis at diagnosis in 43 pts, among those 35 pts passed 3 M, 34 pts 6 M and 15 pts 12 M, respectively.Results: MR3.0 rate was 8/35 at 3M, 23/34 at 6M and 10/15 at 12M. When 43 pts were classified into two groups (higher: H, lower: L) according to the mean CD34+ cell counts at diagnosis (5995/mL of BM aspirates), there were significant differences (p<0.05) in BCR-ABL transcripts indicated as IS (77.66 vs 64.03 %, p=0.030) and WBC count (81.3 vs 22.3 /mL, p=0.012), but no differences in molecular responses at 3, 6 and 12 M between the two groups. There was a positive correlation between CD34+ cell count and WBC count (r=0.328, p=0.035).The median percentage of Ph+ cells, as measured by FISH (~1000 cells analyzed), in CD34+CD38- fraction at diagnosis was 97.1% (range 2-100%) compared to 98.6% (range 28.2-99.8%) in CD34+CD38+ fraction. The proportion of Ph+ cells in CD34+CD38- fraction correlated with PLT count (r=0.394, p=0.014) but inversely with RBC count (r=-0.474, p=0.003), Hb (r=-0.587, p=0.0001) and Ht (r=-0.475, p=0.003), respectively. Between the two groups divided by the median percentage, there were significant differences in RBC count (406 vs 460 x104/mL, p=0.046), Hb (11.7 vs 14.5 g/dL, p=0.009) and Hct (38.8 vs 44.7%, p=0.040). There were no significant differences in molecular responses at any check points. On the other hand, when divided by the mean percentage (81.1%), there was only a significant difference in PLT count (48.1 vs 27.2 /mL, p=0.028).Absolute Ph+ cell counts in CD34+CD38- fraction were estimated in each patient by combining 3 parameters of CD34 cell counts/mL of BM aspirates, proportion of CD38- fraction and percentage of Ph+ cells. Ph+CD34+CD38- cell counts siginificantly correlated with WBC count (r=0.365, p=0.021) and inversely with RBC count (r=-0.361, p=0.002), Hb (r=-0.409, p=0.009) and percentage of lymphocytes (r=-0.339, p=0.032). Between the 2 groups divided by the median cell counts (256/mL), there were significant differences in RBC (406.5 vs 472.0 x104/mL, p=0.005), Hb (11.8 vs 14.3 g/dL, p=0.004), Hct (39.0 vs 44.6 %, p=0.024). Although we could not find significant difference in molecular responses at any check points, patients with lower number of Ph+CD34+CD38- cells tend to achieve MR3.0 faster than those with higher number of cells (p=0.059) (Figure 1). When divided by the mean cell counts (578/mL), there was a significant difference in WBC count (94.45 vs 22.44 /mL, p=0.016).Conclusion: increased Ph+ stem cell burden apparently affects the level of leukocytosis and anemia at diagnosis, but not MR3.0/MR4.0 rate by 12 M on nilotinib, although it is likely to extend time to achieve MR3.0. [Display omitted] DisclosuresNishiwaki:Novartis: Research Funding. Sugimoto:Novartis: Speakers Bureau. Shimizu:Novartis: Speakers Bureau. Wakita:Novartis: Speakers Bureau. Tojo:Novartis: Research Funding, Speakers Bureau.

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.

7053^ Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]

Change in Chronic Low-Grade Nonhematologic Adverse Events (AEs) and Quality of Life (QoL) in Adult Patients (pts) with Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Switched From Imatinib (IM) to Nilotinib (NIL)

Change in Chronic Low-Grade Nonhematologic Adverse Events (AEs) and Quality of Life (QoL) in Adult Patients (pts) with Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Switched From Imatinib (IM) to Nilotinib (NIL)

Switch to nilotinib versus continued imatinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up.

6505^ Background: Nilotinib induced significantly faster and deeper molecular responses vs imatinib in the ENESTnd trial. Achieving these deeper molecular responses may increase patient eligibility for future TKI discontinuation studies. Methods: CML-CP pts (N = 207) who achieved a complete cytogenetic response but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg BID (n = 104) or to continue their imatinib dose (400 or 600 mg QD [n = 103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL by RQ-PCR with a sample sensitivity of ≥ 4.5 logs in 2 consecutive samples). Other endpoints included molecular responses (MMR ≤ 0.1%IS, MR4 ≤ 0.01%IS, and MR4.5 ≤ 0.0032%IS) and BCR-ABL ratio over time. Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL in at least 1 sample) by 12 mo was significantly higher on nilotinib vs imatinib (23.1% vs 10.7%; P = .02). Rates of MMR, MR4, MR4.5, and CMR were also superior in pts switched to nilotinib, and these pts had significantly shorter times to achieve these responses. Imatinib-treated pts had minimal evidence of improvement in molecular response vs a median 0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With 12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib. The nilotinib safety profile was consistent with prior studies. Both drugs were well tolerated. Conclusions: Twice as many pts achieved deeper molecular responses after switching to nilotinib vs staying on imatinib. [Table: see text]

Landmark Analysis of Imatinib Treatment in CML Chronic Phase: ES-FISH

Abstract 1702The use of imatinib (ima) and other tyrosine kinase inhibitors (TKI) has dramatically improved the clinical outcome for patients (pts) with chronic myeloid leukemia in chronic phase (CMLcp). Although most pts respond well, there is a subpopulation that fails to reach internationally defined clinical treatment goals, as assessed by techniques such as cytogenetics (CG) and quantitative polymerase chain reaction (PCR). Pts with a poor initial treatment response appear to have an increased risk of subsequent disease progression to accelerated phase or blast crisis, which still constitute a serious medical challenge. It was recently shown that landmark analysis assessing PCR levels after 3 months (mo) of ima treatment was linked to major cytogenetic response (mCyR) at 12 mo and risk of long-term progression (Hanfstein ASH2010 abstract 360). Similar data based on fluorescence in-situ hybridization (FISH) landmark assessment of larger CMLcp pt groups are still lacking.We have followed a cohort of 45 newly diagnosed CMLcp pts, all initiated on ima (400mg qd), by sequentially assessing their treatment responses by CG, PCR and interphase ES-FISH and relating early BCR-ABL expression levels to subsequent clinical response. A complete cytogenetic response (CCyR) was observed in 56% of evaluable pts after 6 mo, 80% after 12 mo and 94% after 24 mo of treatment. Corresponding figures for major molecular response (MMR) were 9%, 47% and 71%, respectively. Early levels of BCR-ABL as assessed by FISH could predict subsequent response. Thus, of patients with FISH-pos ≤10% at 3 mo 95% achieved CCyR at 12 mo, while this response was noted in only 67% of pts with FISH-pos >10% at 3 mo (p=0.042; Fisher’s exact test, n=37). Similarly, all evaluable pts with FISH-pos ≤10% at 3 mo were alive and event-free (EFS) at 36 mo, as compared to 67% EFS at 36 mo among pts with FISH-pos >10% at 3 mo (p=0.008, n=37). Performing similar landmark analyses with FISH ≤ or >10% at 6 and 12 mo also yielded significant differences regarding EFS at 36 mo (p=0.046 and p=0.003, respectively). Employing corresponding landmark analyses with PCR at 3 mo and 6 mo, no significant association to EFS at 36 mo could be detected.In conclusion, our landmark analysis data indicate that ES-FISH can be used effectively already after 3 mo of ima treatment in order to identify a patient cohort with inferior long-term survival and with a higher risk for disease progression. FISH can unlike CG, be efficiently performed on peripheral blood cells which facilitates its clinical use. In comparison to PCR earlier data have shown that FISH, although less sensitive, may be more reliable and reproducible at higher BCR-ABL expression levels, typically seen in the early treatment phase. This may explain the superior outcome of early landmark analysis using FISH, as compared to PCR, in our study. Expanded trials on larger CMLcp pt cohorts are warranted to further clarify the prognostic value, and possible impact on early treatment alterations, of early FISH analyses during TKI treatment. Disclosures:No relevant conflicts of interest to declare.

Complete Molecular Response (CMR) Rate with Nilotinib in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) without CMR After ≥ 2 Years on Imatinib: Preliminary Results From the Randomized ENESTcmr Trial of Nilotinib 400 Mg Twice Daily (BID) Vs Imatinib

Abstract 606 Background: Recent studies have demonstrated that about 40% of very highly selected CML-CP pts treated with imatinib achieve durable CMR and may be able to cease therapy without disease recurrence. However, most CML pts don9t achieve CMR on imatinib even with long-term therapy. Results from ENESTnd demonstrated that significantly more patients achieved MMR (≤ 0.1%IS), CMR4 (≤ 0.01%IS), and CMR4.5 (≤ 0.0032%IS) with nilotinib vs imatinib by 12, 18, and 24 months (mo). No pt in ENESTnd who achieved CMR4.5 has progressed to AP/BC. In this study we asked whether pts on long-term imatinib would be more likely to achieve undetectable BCR-ABL levels if they switched to nilotinib, allowing for participation in potential cessation studies in the future. Methods: This open label, 1:1 randomized, prospective, multi-center, phase 3 study enrolled 207 pts with CML-CP who had achieved a complete cytogenetic response (CCyR) but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib. CMR (primary endpoint) was defined as undetectable BCR-ABL by RQ-PCR where there was no detectable BCR-ABL with a sample sensitivity of ≥ 4.5-logs. CMR4 and CMR4.5 were defined as BCR-ABL levels of ≤ 0.01% and ≤ 0.0032% expressed on the International Scale (IS), respectively and included patients with undetectable BCR-ABL levels with high sample sensitivity (4 or 4.5 logs). Patients were randomized to nilotinib 400 mg BID vs continuing imatinib 400 or 600 mg daily (same dose as at study entry.) The randomization was stratified by prior use of IFN (none, ≤ 12 mo, > 12 mo) and prior duration of imatinib therapy (> 36 mo or ≤ 36 mo). The primary endpoint was the rate of confirmed best cumulative CMR by 12 mo of study therapy with nilotinib or imatinib. Secondary objectives included the kinetics of CMR at different timepoints, duration of CMR, progression-free survival, and overall survival in both arms. During the study, RQ-PCR for BCR-ABL was performed at baseline (BL) and every 3 mo and expressed on the IS in national reference laboratories in Australia, Brazil, and Canada. For this report: BL, 6 mo, and 12 mo results were analyzed in a central laboratory in Australia. Assessment of the primary efficacy endpoint has not been completed for 2% of the randomized pts; unblinded data will be available for all pts and will be presented by treatment arm. Results: BL results were available for 205/207 randomized pts. Overall, 56% of pts had no prior IFN exposure, while 21% and 23% had IFN exposure of ≤ 12 mo or > 12 mo, respectively; 81% of pts had been on imatinib > 36 mos. At BL, 153 pts (74%) were known to be in MMR and 54 pts (26%) had Disclosures: Hughes:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Lipton:Novartis Pharmaceuticals Canada Inc: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Leber:Novartis Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Spector:Novartis: Membership on an entity9s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; BMS: Speakers Bureau. Pasquini:Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Schwarer:Novartis: Honoraria; BMS: Honoraria. Mahon:Novartis: Honoraria, Research Funding. Rea:BMS: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Kamel-Reid:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Reynolds:Novartis: Employment, Equity Ownership. Williams:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Branford:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding.

Effect of Switching to Nilotinib in Patients with Imatinib-Related Low-Grade Non-Hematologic Adverse Events

Effect of Switching to Nilotinib in Patients with Imatinib-Related Low-Grade Non-Hematologic Adverse Events

Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs) on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

Abstract 2768 Background:24-month follow-up of pts with newly diagnosed CML-CP in the DASISION trial demonstrated both a high rate of complete cytogenetic response (CCyR) with dasatinib (D) and higher and faster rates of major molecular response (MMR) with D over imatinib (IM), supporting the use of D 100 mg once daily as a first-line treatment option for newly diagnosed CML-CP. Discontinuations due to adverse events (AEs) occurred in 7% with D and 5% with IM. Median dose intensity for D and IM were 99.5 mg/day and 400 mg/day, respectively (Kantarjian JCO 2011:29;Abs 6510). A retrospective analysis of pts from DASISION was performed to evaluate the impact of dose reductions and interruptions due to AEs on efficacy of D or IM in newly diagnosed CML-CP. Methods:Pts with newly diagnosed CML-CP received D 100 mg QD (N=258) or IM 400 mg QD (N=258). The primary endpoint was confirmed CCyR by 12 months. In DASISION, up to two dose reductions were permitted for AEs; dose reduction levels were 80 mg/50 mg for D and 300 mg/200 mg for IM. Dose interruptions were permitted for management of AEs. Upon resolution or improvement of AEs to ≤ Grade 1, pts could resume therapy at an appropriate dose based on initial severity of the AE. Efficacy was evaluated for pts with or without dose reductions and/or interruptions due to AEs at any time. Efficacy was also evaluated for pts with first dose interruption and/or reduction due to AEs within ≤6 or >6 months of their first dose who remained on treatment for at least 6 months, in order to reduce selection bias of pts with longer duration of therapy. Pts with dose reduction and/or interruption for reasons other than AEs (dosing error, medical procedure) were excluded from all analyses. Results:134 D pts (52%) and 92 IM pts (36%) had dose reduction and/or interruption for AE management at the DASISION 24-month update. First dose reduction and/or interruption due to non-hematologic AEs occurred in 59 (23%) D and 40 (16%) IM pts and hematologic AEs in 75 (29%) D and 52 (20%) IM pts. Pts with dose reduction and/or interruption for reasons other than AE management were excluded, including 21 (8%) D pts and 19 (7%) IM pts. The median duration of first dose interruption due to AEs was approximately 2 weeks on both arms. CCyR and MMR rates with D were comparable whether pts did or did not have their dose reduced and/or interrupted at any time (Table). D pts who had dose reduction and/or interruption had generally higher rates of responses than IM pts overall and in those without an IM dose reduction and/or interruption. The timing of dose reduction and/or interruption appeared to have a potential impact as response rates were higher when dose reduction and/or interruption occurred >6 months after the first dose of either drug (Table). CCyR and MMR rates with D remained higher than with IM when dose reduction and/or interruption occurred ≤6 months from first dose. Similarly, both CCyR and MMR were higher for D than with IM if dose reduction and/or interruption occurred >6 months from the first dose. Conclusions:Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib.All TreatedNo Dose R and/or IDose R and/or I due to AEaD N=258IM N=258D n=103IM n=147D n=134IM n=92CCyR by 12 mo221 (86%)191 (74%)89 (86%)111 (76%)107 (80%)59 (64%)CCyR by 24 mo223 (86%)213 (83%)90 (87%)126 (86%)112 (84%)69 (75%)MMR by 12 mo119 (47%)73 (28%)50 (49%)43 (29%)55 (41%)21 (23%)MMR by 24 mo165 (64%)120 (47%)71 (69%)66 (45%)76 (57%)41 (45%)2-year PFS94%92%94%90%93%93%2-year OSc95%95%97%93%94%98%R and/or I due to AE ≤6 Months After 1st DosebR and/or I due to AE >6 Months After 1st DoseD n=90IM n=61D n=34IM n=24CCyR by 12 mo76 (84%)39 (64%)29 (85%)18 (75%)CCyR by 24 mo80 (89%)47 (77%)30 (88%)20 (83%)MMR by 12 mo35 (39%)14 (23%)20 (59%)7 (29%)MMR by 24 mo53 (59%)26 (43%)23 (68%)15 (63%)2-year PFS96%96%93%90%2-year OSc98%98%97%100%AE = adverse event; I = interruption; R = reductionaPatients with dose R and/or I due to reasons other than AEs were excluded (21 D, 19 IM)bPatients on treatment ≤6 months were excluded (10 D, 7 IM)cSurvival data remain immature; all patients will be followed for 5 years Disclosures:Kantarjian:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Quintas-Cardama:Bristol-Myers Squibb: Honoraria. Guilhot:Novartis: Honoraria; Bristol-Myers Squib: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Zhu:Bristol-Myers Squibb: Employment. Hong:Bristol-Myers Squibb: Employment, Equity Ownership. Cain:Bristol-Myers Squibb: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 24-month follow-up.

6511 Background: Nilotinib demonstrated superiority vs imatinib in ENESTnd at 12 months (mo). Here, we present data with a minimum follow-up (f/u) of 24 mo. Methods: 846 CML-CP pts were randomized to receive nilotinib 300 mg bid (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg qd (n = 283). Primary endpoint was major molecular response (MMR, ≤ 0.1% BCR-ABLIS) at 12 mo. Here, we report MMR by 24 mo, overall best molecular response (CMR4 and CMR4.5), progression to AP/BC, progression-free survival (PFS), and overall survival (OS). Results: With minimum 24-mo f/u, response rates were significantly higher for nilotinib vs imatinib. MMR rates remained superior for nilotinib across all Sokal risk groups. Achievement of CMR4 and CMR4.5 were significantly higher for nilotinib vs imatinib. There continued to be significantly fewer progressions to AP/BC on treatment, including clonal evolution (CE), on nilotinib 300 (n = 2) and 400 mg bid (n = 5) vs imatinib (n = 17). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths on both nilotinib 300 (n = 5) and 400 mg bid (n = 3) vs imatinib (n = 10). Both drugs were well tolerated. Discontinuation due to adverse events/lab abnormalities was 9% for nilotinib 300 mg bid, 13% for nilotinib 400 mg bid, and 10% for imatinib. Conclusions: Nilotinib continues to demonstrate superior efficacy with significantly improved disease control vs imatinib for the treatment of pts with newly diagnosed CML-CP. Nilotinib 300 mg bid (n = 282) Nilotinib 400 mg bid (n = 281) Imatinib 400 mg qd (n = 283) MMR, % By 24 mo 71* p < .0001* 67* p < .0001* 44 Best molecular response at any time, % ≤ 0.01% IS (CMR4) 44 p < .0001* 36 p < .0001* 20 ≤ 0.0032% IS (CMR4.5) 26 p < .0001* 21 p = .0004* 10 Freedom from progression to AP/BC, (%) Estimated rate at 24 mo Excluding CE 99.3 p = .0059** 98.1 p = .0196** 95.2 Including CE 99.3 p = .0003** 97.3 p = .0089** 93.2 PFS, % Estimated rate at 24 mo OS, % 98.0 p = .0736** 97.7 p = .0437** 95.2 Estimated OS rate at 24 mo 97.4 p = .6485** 97.8 p = .2125** 96.3 Estimated OS rate of CML- related death at 24 mo 98.9 p = .1930** 98.9 p = .0485** 96.7 * Cochran-Mantel-Haenszel test stratified by Sokal vs imatinib. ** Log-rank test stratified by Sokal vs imatinib.

Patients (Pts) with Ph+ Chronic Myeloid Leukemia In Chronic Phase (CML-CP) with a Suboptimal Molecular Response to Imatinib (IM) Can Achieve Deeper Responses When Switched to Nilotinib

Patients (Pts) with Ph+ Chronic Myeloid Leukemia In Chronic Phase (CML-CP) with a Suboptimal Molecular Response to Imatinib (IM) Can Achieve Deeper Responses When Switched to Nilotinib