Higher Rates Of Complete Cytogenetic Response Research Articles

Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients.

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a “real-life” setting.We retrospectively analyzed 163 patients receiving dasatinib (n = 95) or nilotinib (n = 68) as second-line therapy after imatinib. The two cohorts were comparable for disease's characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients.Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib.In a “real-life” setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation.

Influence of BCR-ABL Transcript Type on Outcome in Patients With Chronic-Phase Chronic Myeloid Leukemia Treated WithImatinib.

The prognostic significance of breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) transcripts in chronic myeloid leukemia (CML) is still controversial. All consecutive CML patients in chronic phase treated with imatinib in a single center were analyzed (n= 170). BCR-ABL1 transcript was evaluated using multiplex reverse transcription polymerase chain reaction. Exclusively patients with BCR-ABL transcripts e13a2 and/or e14a2 were included in this analysis. Patients with e14a2 transcripts presented higher rates of optimal molecular responses at 3 months and higher rates of complete cytogenetic response (CCR) at 6 months. E13a2, e14a2, and e14a2 with e13a2 (e14a2+e13a2) groups presented similar rates of 5-year event-free, progression-free, and overall survival. There was a superior 10-year overall survival in patients with transcripts e13a2 compared with e14a2 (alone or coexpressed with e13a2; 93% vs. 73%; P= .03), although the 5-year overall survival was 96% vs. 88%, respectively (P= not significant). In a multivariate analysis, high/intermediate Sokal score and e14a3/e14a3+e14a2 were independent factors for poor overall survival (hazard risk [HR], 4.63; P= .023 for Sokal score and HR, 10.6; P= .041 for BCR-ABL transcript). Patients with BCR-ABL transcripts e14a2 transcripts have higher rates of CCR at 6 months and higher rates of optimal molecular response at 3 months compared with e13a2 or with both transcripts, but no difference in 5-year overall, progression-free, and event-free survival. There was a superior 10-year overall survival among patients with transcripts e13a2 compared with e14a2 (alone or coexpressed with e13a2).

Impact Of The Achievement Of a Complete Cytogenetic Response (CCyR) On Outcome In Patients (pts) With Myelodysplastic Syndromes (MDS) Treated With Hypomethylating Agents (HMA)

BackgroundEpigenetic therapy with HMA is now the standard of care for pts with MDS with complete response (CR) rates of 7% to 35% and median survival of 20 to 24 months (mos). Large studies have demonstrated the relevance of karyotype abnormalities as an independent prognostic factor in predicting outcome in MDS pts. In pts with chronic myeloproliferative neoplasms (e.g. chronic myeloid leukemia), the achievement of CCyR has proven to correlate with improved outcomes: less transformation into acute myeloid leukemia and better overall survival. However this phenomenon has not been examined thus far in pts with MDS, where the response criteria are still predominantly based on morphologic basis. AimsTo assess the impact of CCyR on outcome in pts with MDS treated with HMA Methods216 consecutive pts with MDS and abnormal karyotype treated with HMA between 4/04 and 10/12 were reviewed. Response criteria were based on the International Working Group (IWG) 2006 criteria. CCyR was defined as achievement of a diploid karyotype among at least 20 metaphases analyzed. ResultsMedian age was 66 years (21-90). IPSS was high-risk in 22%, intermediate-2 in 55%, intermediate-1 in 21%, and low-risk disease in 3%. 54% were secondary MDS; 43% were therapy-related MDS. Cytogenetic analysis revealed a complex karyotype in 24%, predominantly demonstrating abnormalities in chromosomes 5 or 7 (37%) and other abnormalities (39%). 69% were treated with decitabine based therapy (single agent in 47%) while 31% were treated with 5-azacitidine (single agent in 20%). Best responses were CR in 64 pts (33%), CR without platelet recovery (CRp) in 15 pts (8%), partial response (PR) in 4 pts (2%), hematologic improvement (HI) in 10 pts (5%), and stable disease (SD) in 5 pts (3%). Furthermore, CCyR was achieved in 68 pts (31%): 45/79 pts with CR/CRp (57%), 3/19 pts with PR/HI/SD (16%), and 20/118 pts with no morphologic response (17%) (p<0.01). In addition, higher rates of CCyR were observed among pts with intermediate-2 risk disease (IPSS) compared to those with high-risk disease (68% vs 18%; p=0.02) and among pts with de-novo MDS compared to therapy-related MDS (68% vs 32%; p=0.05). By multivariate analysis, clinical parameters associated with the achievement of CCyR were morphologic CR/CRp (OR=4.24; p<0.001) and therapy related MDS (OR=0.40; p=0.01). Median follow-up was 43 mos (range 34-57). Median overall survival (OS) and transformation-free survival (TFS) were 14 and 10 mos respectively. The 2-year OS and TFS rates were 25% and 18%, respectively. The median OS and TFS for pts with and without CCyR were 20 and 11 mos (p=0.007), and 14 and 9 mos (p=0.039) respectively. Pts who achieved CCyR in addition to their morphologic CR/CRp had a trend for better outcome compared to pts who achieved morphologic CR/CR only, with a median OS of 18 mos versus 15 mos (p=0.42), respectively, and a median TFS of 14 mos versus 9 mos (p=0.32). ConclusionOur results indicate that CCyR can occur at a rate of 31% in pts with MDS treated with HMA. Pts presenting with primary MDS and attaining a morphologic response to HMA are more likely to achieve a CCyR. Furthermore we identified a significant association/correlation between the achievement of CCyR and better OS and TFS, independent of attaining a morphologic response. Therefore, the achievement of CCyR should be considered a new milestone in the management of pts with MDS. Disclosures:No relevant conflicts of interest to declare.

The Association Of Dasatinib-Induced Lymphocytosis With Treatment Outcome In Patients With Chronic Myeloid Leukemia (CML)

The Association Of Dasatinib-Induced Lymphocytosis With Treatment Outcome In Patients With Chronic Myeloid Leukemia (CML)

Frontline Nilotinib Results In Superior Rates Of Molecular Response Versus Imatinib In Chinese Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP): ENESTchina 12-Month Primary Analysis

BackgroundIn global clinical trials, nilotinib has shown superior efficacy vs imatinib for treating patients (pts) with CML-CP. The Evaluating Nilotinib Efficacy and Safety in Clinical Trials–China (ENESTchina) study is assessing the efficacy and safety of frontline nilotinib vs imatinib in Chinese pts with CML-CP. MethodsENESTchina (NCT01275196) is a multicenter, open-label, phase 3 study of Chinese adults with newly diagnosed (≤ 6 mo) CML-CP. Pts were randomized to nilotinib 300 mg BID (n = 134) or imatinib 400 mg QD (n = 133). The primary endpoint was the rate of major molecular response (MMR; ≤ 0.1% BCR-ABL on the international scale) at 12 mo. Molecular assessments were performed at a central laboratory. This analysis was conducted when all randomized pts had ≥ 12 mo of follow-up or discontinued early. ResultsBaseline characteristics were similar between the arms (Table). Most pts (nilotinib, 93%; imatinib, 95%) remained on treatment at the data cutoff. Median actual dose intensities were nilotinib 565 mg/day (range, 167-600 mg/day) and imatinib 393 mg/day (range, 204-550 mg/day). Sixteen pts (nilotinib, n = 9; imatinib, n = 7) discontinued, mainly due to adverse events (AEs; nilotinib, n = 3; imatinib, n = 1), withdrawal of consent (nilotinib, n = 3; imatinib, n = 1), or disease progression (nilotinib, n = 2; imatinib, n = 2).The primary endpoint was met, with a significantly higher rate of MMR at 12 mo in the nilotinib arm vs the imatinib arm (52% vs 28%, respectively; P < .0001). The MMR rate at 12 mo was higher in the nilotinib arm vs the imatinib arm across all Sokal risk groups (Table). The rate of complete cytogenetic response (CCyR) by 6 mo was higher in the nilotinib arm vs the imatinib arm, but by 12 mo CCyR rates were similar in both arms. By the cutoff date, 2 pts (1.5%) in each arm had progressed to accelerated phase/blast crisis (AP/BC) on treatment. Three deaths were reported (all ≥ 28 days after discontinuing treatment), 2 in the nilotinib arm (due to cerebral hemorrhage [n = 1] and study indication [n = 1]) and 1 in the imatinib arm (due to recurrent non-Hodgkin lymphoma).There was no difference between the arms in time to progression to AP/BC on treatment or overall survival.Both drugs were well tolerated, with safety profiles similar to those reported in prior studies. The most common AEs on nilotinib were rash and myalgia; on imatinib, fluid retention and nasopharyngitis were most common (Table). One pt in the imatinib arm had a grade 1 increase in creatine phosphokinase-MB with no clinical signs indicative of ischemic heart disease. No cases of peripheral arterial occlusive disease, ischemic cerebrovascular events, or QTcF > 480 ms were observed in either arm. Newly occurring/worsening grade 3/4 thrombocytopenia and neutropenia occurred at similar rates in both arms, while leukopenia, lymphopenia, and anemia were more frequent in the imatinib arm. The most common newly occurring/worsening grade 3/4 biochemical abnormality in both arms was elevated lipase. ConclusionsIn Chinese pts with newly diagnosed CML-CP, nilotinib was well tolerated and demonstrated superior efficacy over imatinib, as shown by higher rates of MMR in all Sokal risk groups, despite similarly high rates of CCyR after 1 y with both drugs. These results highlight the utility of MMR as a more sensitive efficacy endpoint for differentiating tyrosine kinase inhibitors in pts with CML-CP and provide the first evidence-based, prospective confirmation of the superiority of nilotinib over imatinib observed in the ENESTnd trial. Disclosures:Wang:Novartis: Employment; Bristol Myers Squibb: Consultancy. Baccarani:Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jevtic:Novartis: Employment, Equity Ownership. Ortmann:Novartis: Employment. Yuan:Novartis: Employment. Menssen:Novartis: Employment. Saglio:ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Baseline Predictors of Response to Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia Following Resistance or Intolerance to Imatinib Plus Dasatinib and/or Nilotinib.

AbstractAbstract 2793Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated the activity and tolerability of BOS 500 mg/d in Philadelphia chromosome–positive (Ph+) leukemia following prior TKI exposure. The current analysis investigated baseline characteristics as predictors of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), and 2-year Kaplan- Meier–estimated progression-free survival (PFS) and overall survival (OS).All included patients had chronic phase (CP) chronic myeloid leukemia (CML), had developed resistance/intolerance to prior imatinib, and were also either dasatinib resistant (n = 38), dasatinib intolerant (n = 50), nilotinib resistant (n = 27), nilotinib intolerant (n = 1), or resistant/intolerant to dasatinib and nilotinib (n = 3). Median follow-up was 31.4 mo (range, 0.3–66.0 mo). A summary of results is provided in the Table.Longer time since CML diagnosis versus shorter time (median time 6.61 years) was associated with greater OS (2-y probability, 90% vs 79%; log-rank P= 0.0435); however, no association with MCyR, CCyR, or PFS was observed.A lower percentage of Ph+ cells (<95% Ph+ cells vs ≥95% Ph+ cells) at baseline was significantly associated with a higher rate of MCyR (76% vs 23%; P <0.001) and CCyR (65% vs 14%; P <0.001), as well as PFS (2-y probability, 83% vs 68%; log-rank P = 0.0181); no association with OS was observed.Resistance versus no resistance (ie, only intolerance) to prior TKIs was not significantly associated with response or survival, although a numeric trend toward lower rates of MCyR (39% vs 50%) and CCyR (28% vs 50%), as well as 2-y probabilities of PFS (72% vs 89%) and OS (82% vs 91%) among resistant patients was observed.Prior response of at least a minor cytogenetic response (MiCyR) versus no response to first-line imatinib was associated with a higher rate of MCyR (49% vs 28%; P= 0.0375) and a numeric trend toward a higher rate of CCyR (39% vs 20%) on BOS; no trend for PFS or OS was observed. Prior response of at least MiCyR versus no response to second-line dasatinib/nilotinib was associated with higher rates of MCyR (56% vs 19%; P<0.001) and CCyR (48% vs 7%; P<0.001), as well as PFS (2-y probability, 80% vs 64%; log-rank P= 0.0180) and OS (2-y probability, 89% vs 77%; log-rank P= 0.0285) on BOS.While baseline demographic characteristics showed a numerical trend toward lower response and/or survival rates with age ≥65 y and female gender, no trends were statistically significant. There was also no predictive effect for presence of a Bcr-Abl kinase domain mutation at baseline or CP status at onset of imatinib therapy.In conclusion, most evaluated baseline characteristics appeared not to be predictive of response and/or survival on BOS in patients with CP CML and resistance/intolerance to multiple prior TKIs, although at least MiCyR to prior dasatinib/nilotinib and lower percentage of Ph+ cells at baseline were found to be consistently predictive of better outcomes on BOS.n/n evaluable (%)Kaplan-Meier estimate, %nMCyRaCCyRaPFS at 2 yearsOS at 2 yearsAge≥65 y267/22 (32)5/22 (23)7080<65 y9338/88 (43)30/88 (34)7685SexFemale6623/61 (38)17/61 (28)7783Male5322/49 (45)18/49 (37)7386Time since CML diagnosis*≥6.61 y6023/57 (40)17/57 (30)7990<6.61 y5922/53 (42)18/53 (34)7179Status at onset of imatinibbEarly CP4417/39 (44)15/39 (39)7178Late CP7528/71 (39)20/71 (28)7788Percentage of Ph+ cells at baseline*****≥95% Ph+ cells6615/66 (23)9/66 (14)6883<95% Ph+ cells4328/37 (76)24/37 (65)8385Baseline Bcr-Abl mutationNo4618/45 (40)15/45 (33)8088Yes4014/37 (38)8/37 (22)7780Prior response to imatinib*No response4411/40 (28)8/40 (20)7688At least MiCyRc6028/57 (49)22/57 (39)7887Prior response to dasatinib/nilotinib******No response336/31 (19)2/31 (7)6477At least MiCyRc6735/63 (56)30/63 (48)8089Resistance to prior TKINo2310/20 (50)10/20 (50)8991Yes9635/90 (39)25/90 (28)7282aCumulative response rates.bPatients were considered to be in late CP at the moment of starting imatinib if they had commenced imatinib ≥6 mo after diagnosis or had received prior interferon therapy; other patients were considered to be in early CP.cDefined as <15% blasts in bone marrow and blood, <30% blasts + promyelocytes in bone marrow and blood, and <20% basophils in peripheral blood with no extramedullary disease other than spleen and liver.*P value <0.05;**P value <0.001. Disclosures:Cortes:Novartis, Bristo Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Kantarjian:Pfizer Inc: Research Funding.

EUTOS Score Is Not Predictive for Survival and Outcome in Patients (pts) with Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKIs) At MD Anderson Cancer Center (MDACC),

Abstract 3769 Background:Until recently, prognosis of pts with CML treated with TKI was based on scores developed in the chemotherapy and interferon era. Hasford and colleagues [Blood. 2011;(118):686–692] have identified the EUTOS score, using the percentage of basophils and spleen size, as a significant tool to predict the probability of achieving 18-month complete cytogenetic response (CCyR) and progression-free survival in patients treated with imatinib. Aims:To validate the EUTOS score in an independent MDACC cohort of pts, with early CML-CP treated with standard-dose imatinib, high-dose imatinib, dasatinib, and nilotinib, and its ability to predict transformation-free survival (TFS), event-free survival (EFS) and overall survival (OS). Methods:465 consecutive pts with newly diagnosed CML–CP (0 – 6 months from diagnosis to TKI treatment) were treated with imatinib 400 mg daily (n=71), imatinib 800 mg daily (n=208), and 2nd TKIs (n=186; dasatinib n=88, nilotinib n=98) in sequential phase II trials. Entry criteria were similar for all trials. EUTOS score = (7 x basophils %) + (4 x spleen cm BCM). A EUTOS score of >87 indicates high-risk and ≤87 low-risk. Results:465 pts with CML-CP were assessed. Median age was 47 years (range, 15–85). Median time from diagnosis to TKI therapy was 1 month (range, 0 to 6). 319 (69%), 112 (24%), and 34 (7%) pts were in low, intermediate, and high-Sokal score category, respectively. Median basophils percentage at baseline was 3 (range, 0 to 19). Median splenomegaly size was 0 cm (range, 0 to 30). 118 pts (25%) received previous cytoreduction therapy. Median follow-up was 117 months (range, 16 to 130) for pts receiving standard-dose imatinib, 88 months (range, 4 to 118) for those receiving high-dose imatinib, and 30 months (range, 3 to 69) for those receiving 2nd TKI. The overall CCyR rates were 87%, 91%, and 95%, respectively. The 4-year EFS, TFS, and OS rates for the whole group were 84%, 94%, and 95%, respectively. Overall, of the 465 pts, 427 (92%) were in low EUTOS score category (Table 1). Pts with low EUTOS score had higher rates of CCyR at anytime compared to pts with high EUTOS score (93% versus 81%, p=0.02). This difference was mainly significant among pts receiving 2nd TKI (p=0.03) while it was not different among pts receiving imatinib (p=0.27). There was no difference in the rates of major molecular response (85% versus 81%, p=0.48) between pts with low and high EUTOS score. There was no difference in TFS, EFS, and OS rates between pts with low and high EUTOS score, overall and among specific therapy (Table 1). Conclusion:Eight percent of pts with CML-CP treated at MDACC are of high EUTOS score. In this population, the EUTOS score was not predictive for overall MMR, TFS, EFS, and OS.ParameterOverallLow EUTOS scoreHigh EUTOS scorep-valueN=465427 (92%)38 (8%)CCyR (%)Overall (evaluable=454)9293810.02 Imatinib9091820.27 400 mg87861001.0 800 mg9192790.082nd TKI9596800.03MMR (%)Overall (evaluable=452)8585810.48 Imatinib8485820.76 400 mg78771001.0 800 mg8687790.302nd TKI8686800.464-year EFS (%)Overall8484810.71 Imatinib8182720.20 400 mg7880500.34 800 mg8283760.292nd TKI89881000.164-year TFS (%)Overall9494970.51 Imatinib9393940.33 400 mg8990670.47 800 mg94931000.462nd TKI97971000.534-year OS (%)Overall95951000.88 Imatinib94941000.75 400 mg93921000.34 800 mg95941000.322nd TKI99991000.64 Disclosures:Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Analysis of the GeneXpert System on the International Multicentre ICORG 08–02 Phase II Study of Nilotinib 300mg BID as Frontline Treatment in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECPCML),

Abstract 3774 BACKGROUND/METHODS:Data from the ENESTnd phase III trial showed superiority of nilotinib over imatinib leading to accelerated approval of nilotinib as initial treatment of ECPCML at a dose of 300mg BID. ICORG, the All-Ireland Cooperative Oncology Research Group, has been coordinating an international open-label, single stage, multicenter, investigator-initiated phase II study (ClinicalTrials.gov NCT00809211) of the safety and efficacy of nilotinib 300 mg BID in previously untreated patients with ECPCML. The primary study endpoint is the complete cytogenetic response (CCyR) rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a novel rapid turnaround PCR system “GeneXpert” with IS BCR-ABL1/ABL1 RQ-PCR. The study closed to accrual with 61 patients (median age 54 years [range 20 –77]) enrolled; 53% have low risk Sokal score, 25% intermediate and 22% high risk. Median follow up is currently 12 months (range 1–30) and by November 2011 all patients will have had at least 6 months follow up. RESULTS:At the time of this analysis, 6 and 12 month follow up data were available in 43 and 31 patients, respectively. By intention to treat analysis, 41/43 (95%) have achieved CCyR within 6 months with all patients still on treatment at 12 months achieving CCyR. 26/43 (60%) and 25/31 (81%) of patients have achieved a major molecular response (MMR) (BCR-ABL1/ABL1 IS ≤ 0.1%) within 6 and 12 months, respectively, with 16/31 (52%) and 11/31 (35%) patients on treatment at least 12 months achieving BCR-ABL1/ABL1 IS ≤ 0.01% and ≤ 0.0032%, respectively. Sokal risk had no apparent effect on response with 12/16 (75%) low risk and 13/15 (87%) intermediate/high risk patients achieving MMR within 12 months, p=0.65. Thus far 4/6 (67%) high risk Sokal patients achieved BCR-ABL1/ABL1 IS ≤ 0.0032% within 12 months. No patients have suffered CML progression to date. 53 patients remain on study. Six patients have been removed from study due to adverse events: 4 patients due to persistent drug-related toxicity; 2 patients non drug-related events (death due to progressive multiple system atrophy and colorectal carcinoma, respectively). In addition, one patient was enrolled but never received study drug and an additional patient was lost to follow up. Treatment was generally well tolerated and toxicities easily managed. Haematologic toxicity was minimal with grade III/IV thrombocytopenia seen in 3 (5%) patients and only a single patient (2%) each with grade III/IV neutropenia and anemia, respectively. The most common grade III/IV non-haematologic toxicity was lipase elevation, seen in 14/61 (23%). No cases of acute pancreatitis were seen. Other grade III/IV non-hematologic toxicities were uncommon (< 5% patients). While treatment was interrupted at least once in 36/59 (61%) patients, the median duration of interruptions was short (5 days). At last follow up 49/59 (83%) of patients were taking ≥ 300mg BID. The study evaluation of the “GeneXpert” PCR system consisted of paired BCR-ABL1/ABL1 measurements performed by RQ-PCR methodologies aligned to International Standard (IS) and by the Xpert BCR-ABL Monitor system on 36 evaluable patients at diagnosis and at 128 subsequent three-monthly time-points. In patients expressing e13a2 or e14a2 BCR-ABL1 transcripts, both techniques had comparable results at diagnosis: IS median BCR-ABL1/ABL1 41.0% vs 44.0% median BCR-ABL1/ABL1 on the Xpert BCR-ABL Monitor. In the 122 paired analyses, correlation between methodologies, without automated system IS conversion, over a five log range (IS BCR-ABL1/ABL1 100–0.001%) was favourable (r2=0.845), however a progressive decline in correlation was noted with each decreasing log IS BCR-ABL1/ABL1 level. No significant difference was observed between the Xpert BCR-ABL Monitor and IS RQ-PCR in identifying MMR (44.3% vs 41.8%). CONCLUSION:In ECPCML, nilotinib 300mg BID induces high rates of CCyR and MMR with a substantial fraction of patients achieving responses in the range of complete molecular response (CMR). This regimen's toxicity is modest. The GeneXpert system provides a reliable and rapid means of assessing CML patients' response to tyrosine kinase inhibitor (TKI) therapy. Development of a reagent lot-specific conversion factor to the IS would enhance GeneXpert's applicability in monitoring TKI therapy in patients with CML. Disclosures:O'Dwyer:Novartis: Honoraria, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau. Nagler:Novartis: Honoraria, Research Funding. Egan:Novartis: Employment. Conneally:Novartis: Honoraria.

First-line Therapy for Chronic Myeloid Leukemia: New Horizons and an Update

Although imatinib has shown unprecedented efficacy in the treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML), approximately one third of patients could benefit from a more effective treatment strategy. Several trials of next-generation agents and modified imatinib-based treatments are in progress, with the aim of improving on standard imatinib 400 mg per day therapy. In the post-imatinib era, a range of assessments are available for evaluating novel strategies. Based on existing evidence, achieving a complete cytogenetic response (CCyR) within 12 months provides the best prediction of longer-term benefit, although durable response and freedom from disease progression are the main treatment goals. In phase II studies, first-line treatment with dasatinib 100 mg once daily or nilotinib 400 mg twice daily resulted in high rates of CCyR and major molecular response (MMR) compared with historical data, and separate phase III trials are ongoing to compare each of these agents with imatinib for the treatment of newly diagnosed CP-CML. Preliminary results indicated higher 12-month CCyR and MMR and lower progression rates for nilotinib compared with standard-dose imatinib. Conflicting findings were reported regarding the ability of high-dose imatinib (800 mg per day) or imatinib plus interferon to induce higher response rates compared with standard-dose imatinib, although no improvement in progression-free survival or overall survival was reported. In the absence of trials comparing novel strategies, the synthesis of emerging data from next-generation agents and modified imatinib-based strategies is likely to be a key area of debate during the next few years.

Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia.

Dasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase. Patients with newly diagnosed CML in early chronic phase were randomly assigned to receive dasatinib 100 mg once daily or 50 mg twice daily as initial therapy. Among 50 patients observed for at least 3 months, 49 patients (98%) achieved a complete cytogenetic response (CCyR), and 41 patients (82%) achieved a major molecular response (MMR). Responses occurred rapidly, with 94% of patients achieving CCyR by 6 months. There was no difference in response rate by treatment arm. The projected event-free survival rate at 24 months is 88%, and all patients are alive after a median follow-up time of 24 months. Grade >or= 3 neutropenia and thrombocytopenia occurred in 21% and 10% of patients, respectively. Nonhematologic toxicity was usually grade 1 to 2. There was no significant difference in toxicity between the two arms, and the actual median dose at 12 months was 100 mg (range, 20 to 100 mg). Dasatinib is an effective agent for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR.

24 Months Update of the TOPS Study: a Phase III, Randomized, Open-Label Study of 400mg/d (SD-IM) Versus 800mg/d (HD-IM) of Imatinib Mesylate (IM) in Patients (Pts) with Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

24 Months Update of the TOPS Study: a Phase III, Randomized, Open-Label Study of 400mg/d (SD-IM) Versus 800mg/d (HD-IM) of Imatinib Mesylate (IM) in Patients (Pts) with Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Outcome, Prognostic Factors and Long-Term Follow-Up in 207 Chronic Phase CML Patients Receiving Front-Line Imatinib 400 mg at a Single Institution.

Imatinib is remarkably effective as single-agent treatment of newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) but most of the published data are based on a single multicenter study (acronym IRIS) carried out under the supervision of the manufacturer. We report here an independent validation of the IRIS results. At our institution from June 2000 and August 2006 207 consecutive newly diagnosed CML-CP patients were started on imatinib 400mg within 6 months from diagnosis, of whom 17 were included in the IRIS study. Their median age was 46.3 years. Their Sokal risk score was ‘low' in 59 (28.5%) patients, ‘intermediate' in 73 (35.3%) and ‘high' in 54 (26.1%). The median follow-up was 33 months (range 12–85). By intention to treat analysis the estimated overall survival (OS) and progression-free survival (PFS, defined by progression to accelerated or blastic phase) at 48 months were respectively 90.5% (95CI, 82.1–95.2%) and 90.2% (95CI, 84.5–94.0%) (data censored at the time of allografting). 34 (16%) patients discontinued imatinib at some point while still in CP and received a second generation TK inhibitor or an allograft. The cumulative incidence of complete cytogenetic response (CCyR) and major molecular response (MMolR) were 59.1% (95CI, 52.0–65.9%) and 11.9% (95CI, 8.0–17.4%) by 12 months, and 86.7% (95CI, 79.4–91.7%) and 58.4% (95CI, 47.6–68.5%) by 48 months respectively (data censored at the time of changing to another treatment). The cumulative incidence of loss of CCyR at 48 months was 17.5% (95CI, 9.9–29.1%). The imatinib dosage was increased in 70 (33.8%) patients to 600 mg/day and in 19 (11.6%) patients the dose was further increased to 800 mg/day during follow-up; in 5(2%) patients the dose of imatinib was directly escalated to 800mg/day. The only pre-therapy factor found to be predictive for PFS was the Sokal (and also Euro) score. A 12-month landmark analysis showed that patients who achieved a CCyR had significantly better OS and PFS at 48 months (OS - 95.2% vs 87.1%, p=0.026; PFS - 97.8% vs 87.3%, p=0.007 respectively), while the achievement of a MMolR by 18 months had no significant impact on OS or PFS. Nevertheless patients in CCyR who achieved a MMolR at any time during the follow-up were significantly less likely to lose their CCyR than CCyR patients who maintained higher BCR-ABL transcript levels (RR=0.08, p=0.0003). No plateau was seen either in the OS or in the PFS curves; however when analysis was restricted to patients who were on CCyR at 12 months the OS and PFS curves did achieve plateaux. Five patients (2.4%) achieved a complete molecular response (CMolR) during the follow up. When restricting the analysis to the 31 patients who had at least 4 years of follow-up only 2 patients (6.5%) had a sustained CMolR while on imatinib 400mg/day. In summary our findings confirm the results reported in the recent IRIS update, notably the high rates of CCyR and high rates OS and PFS at 48 months. Moreover, our results suggest that achieving a CCyR before 12 months is strongly associated with better OS, which accords with the recommendations published recently by the European LeukemiaNet. We showed moreover that once a patient has achieved CCyR, a further reduction in the transcript levels to MMolR is still clinically relevant, although the time-frame is not yet clear.

High-Dose (HD) Imatinib Provides Better Responses in Patients with Untreated Early Chronic Phase (CP) CML.

Imatinib (standard dose, SD, 400mg/day) is highly effective in patients with CML in early chronic phase (CP). However, in a phase I study there was clear dose-response correlation and no maximum tolerated dose was identified up to 1000mg/day. Early reports suggested higher response rates with high dose (HD) imatinib (800 mg/day) in this setting. Here we report the long-term follow-up results of high-dose imatinib for patients with CML in early CP. Patients were included from 3 sequential trials: the first included 50 patients all treated with 400mg daily, and 2 subsequent studies included 208 patients all treated at 800 mg daily as the starting dose. There were no differences in pre-treatment characteristics between HD group and SD groups. The median age was 48 years in both groups. Median follow-up was 58 months for SD and 34 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (91% vs 76% in SD group, p=0.002) and these occurred earlier, with 88% achieving a complete cytogenetic response (CGCR) after 6 months of therapy (vs 56% with SD; p<0.00001). The cumulative incidence of major molecular response (MMR) was significantly higher in HD group at 6, 12, 36 and 48 month of follow-up: in HD group, 33%, 58%, 82% and 88% of patients had achieved this response at each time point (vs 2%, 22%, 64% and 67% in the SD group; p<0.00001, <0.00001, 0.01 and 0.002 at respective time point). The cumulative incidence of complete molecular response (CMR) was also significantly higher in HD group at 6, 12, 36 and 48 month of follow-up: in HD group, 8%, 20%, 53% and 66% of patients had achieved this response at each time point (vs 0%, 4%, 27%, and 34% in the SD group; p=0.05, 0.007, 0.003 and 0.0006 at respective time point). Progression-free and transformation-free survivals were significantly better in HD group (p=0.02 and 0.005). Overall survival was excellent in both groups with no difference between them. Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in both groups. The frequency of ≥ grade 3 anemia, neutropenia and thrombocytopenia in HD group was 12, 35, 29%, respectively while those in SD group were 4, 20, and 12%, respectively. The median actual dose in HD group was 800 mg at 24 months, with only 20% (15/75) of patients taking 400 mg or less at 36 months. We conclude that high-dose imatinib therapy in early CP-CML is associated with higher rates of CGCR, MMR and CMR, and these occur earlier, translating into better progression-free and transformation-free survival. Although HD imatinib is overall well tolerated, there is a higher rate of myelosuppression, most frequently occurring during the first weeks of therapy.

Resistance to Imatinib: Mechanisms and Management

Imatinib, a specific small molecule inhibitor of the Abl kinase, has become the standard drug therapy for chronic myelogenous leukemia in all phases. More than 80% of newly diagnosed patients with chronic phase attain a complete cytogenetic response (CCR). Although remissions in patients with early disease are generally durable, acquired resistance after an initial response is common in advanced disease. Reactivation of Bcr-Abl signaling is almost invariably present at the time of relapse, consistent with re-establishment of the initial pathogenetic mechanism. Mutations in the kinase domain (KD) of Bcr-Abl that impair drug binding and increased expression of Bcr-Abl have been identified as major mechanism of acquired drug resistance. The fact that Bcr-Abl remains central to disease pathogenesis at the time of relapse implies that it also remains the optimal drug target. Alternative Abl kinase inhibitors with increased potency and activity against most Bcr-Abl KD mutants are currently undergoing phase I/II clinical testing, with encouraging early results. Despite the high rates of CCR, persistence of residual leukemia as assessed by reverse transcription polymerase chain reaction is the rule even in patients with chronic phase, suggesting that even these patients may remain at risk of relapse. Understanding the mechanisms underlying disease persistence will be crucial for developing strategies to eradicate residual leukemia.

Long‐term survival estimates for imatinib versus interferon‐α plus low‐dose cytarabine for patients with newly diagnosed chronic‐phase chronic myeloid leukemia

The authors estimated survival among patients with chronic myeloid leukemia for a cost-effectiveness analysis of imatinib versus interferon-alpha plus low-dose cytarabine (IFN+LDAC). Two-year survival and cytogenetic response were determined using data from 553 patients who received first-line imatinib in the International Randomized Interferon versus ST571 Study (IRIS). Long-term survival was modeled on complete cytogenetic response (CCyR) after 2 years. Long-term survival for patients with a CCyR was modeled using data from a cohort study of 317 patients with CCyRs. Long-term survival for patients without a CCyR was modeled using data from a trial of 275 patients who were treated with IFN+LDAC. Computation of lifetime survival estimates for imatinib assumed a proportional hazards relation between survival for an age-matched and gender-matched cohort and survival for patients with and without a CCyR. For IRIS patients receiving imatinib, the estimated survival was 95.8% and the CCyR rate was 73.8%. The average residual life expectancy was estimated to be 16.71 years for CCyR patients and 5.78 years for non-CCyR patients. The estimated life expectancy after treatment with imatinib was 15.30 years, compared with 9.07 years for patients who were treated with IFN+LDAC in previous studies. Assuming the relation between CCyR and survival with interferon-alpha holds for imatinib, higher CCyR rates with imatinib therapy will result in an estimated 6.23 life-years gained compared with treatment with IFN+LDAC.