Incidence Of Complete Cytogenetic Response Research Articles

Very Early Molecular Response at 1 Month Is a Predictor of the Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors

Background The early molecular response (EMR) by tyrosine kinase inhibitors (TKIs) is important to predict optimal response and survival in chronic phase chronic myeloid leukemia (CML-CP). However, EMR achievement can be affected by various clinical factors such as dose intensity, adverse events, blood level and risk scores. However, innate intrinsic sensitivity to TKIs of CML clones has not been considered.Aims To define the optimal molecular response at early time point of treatment initiation with minimal dose interruption, we identified the optimal BCR-ABL1 transcript level measured at 4 weeks after TKI initiation and assessed the clinical impact.Methods In this single center study, 258 newly diagnosed CML-CP patients were treated with various TKIs (130 imatinib and 128 second generation TKIs; 80 dasatinib, 33 nilotinib, 13 radotinib, and 2 bosutinib) and BCR-ABL1 transcript level were analyzed at 4 weeks (28 + 3 days) after frontline TKI initiation.All of patients had e13a2 or e14a2 transcript and a receiver operating characteristic (ROC) curve from BCR-ABL1 transcript level on Day+28 was calculated to predict EMR at 3 months and major molecular response (MMR) at specific timepoints. The results of qRT-PCR were analyzed with at least 4.5-log sensitivity in the central laboratory (Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea).Results Median age was 43 years (18-81 years) and 127 patients were male (Table 1). At 4 weeks, the cut-off values of BCR-ABL1 transcript for achieving 12 month-MMR was 40.89% (very early molecular response; VEMR, P < 0.0001) by ROC curve analysis. One hundred thirty four patients achieving VEMR (<40.89% at 4 weeks) had significantly higher 5-year probabilities of Event-free survival (6.4% vs 13.4 %; P=0.021), cumulative incidence of complete cytogenetic response (89.5% vs 76.8 %; P=0.0001), and complete molecular response (25% vs 11 %; P=0.032) than no VEMR patients. Various predictive factors for achieving VEMR including age, sex, risk score, initial WBC, basophils, splenomegaly, baseline BCR-ABL1 transcript level were analyzed and the data will be presented.Conclusions The very early molecular response defined on the basis of the BCR-ABL1 transcript level measured at 4 weeks of TKI treatment is important for the prediction of long-term responses and survivals. As it also allows for the prediction of CMR, VEMR can be used as one of the important tools to select candidates for treatment free remission. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1

Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1

Clinical results according to age in patients with chronic myeloid leukemia receiving imatinib frontline: The younger, the later, the worse?

To evaluate differences in clinical results according to age among patients with chronic myeloid leukemia (CML). 207 consecutive CML patients treated with imatinib frontline were revised, dividing them in young adults (>20<45years) (YA), middle-aged adults (≥45<65years) (MA) and elderly (≥65years) (EL). Cumulative incidence of complete cytogenetic response (CCyR) and major molecular response (MMolR) were significantly higher in MA compared with YA and EL (P<.001 for CCyR and P=.001 for MMolR). Number of total events was lower in MA (8 [11.1%] vs 21 [34.4%] in YA and 28 [37.8%] in EL, P=.001): no difference was observed for blastic evolution (P=.478). Number of deaths was higher in the EL (12 [16.2%] vs 2 [3.2%] in YA and 0 in MA, P<.001): however, 11/12 deaths in EL were not related to CML. The PFS curve in MA was significantly longer than in YA and in EL (P=.02). The OS curve in EL was significantly shorter than in YA and in MA (P<.001). Age at diagnosis influences significantly the course of CML patients treated with imatinib: a possible explanation of the counterintuitive worse course in YA is the delayed diagnosis compared to elderly.

Impact of the BCR-ABL1 fusion transcripts on different responses to Imatinib and disease recurrence in Iranian patients with Chronic Myeloid Leukemia

BackgroundOne genomic breakpoint can result in variable BCR-ABL1 transcript types due to alternative splicing. The influence of different BCR-ABL1 transcript types on clinical outcome is still controversial. Aim of the studyThe objective of this analysis was to determine the impact of transcript type on response, clinical outcome, recurrence risk after treatment with Imatinib mesylate in Chronic Myeloid Leukemia (CML) patients. MethodsSixty CML patients in chronic phase were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and banding standard protocols. ResultsThere was a significant difference in collective incidence of complete cytogenetic response (CCR) between the e14a2 and e13a2 groups (P=0.04). The median time to achieve CCR was shorter in e14a2 patients than to e13a2 (P=0.01). This finding is paralleled by the molecular response where the median of the BCR-ABL1/ABL1 expression levels were significantly lower in e14a2 transcript compared to e13a2 type at 3, 6, 9 and 12months from the start of therapy (P<0.01). The probability of recurrence after treatment discontinuation was 9.33 fold higher in e13a2 transcript, that is reported here for the first time (χ2=5.49; P=0.01; OR: 9.33; 95% CI: 1.59, 54.67). No significant difference was observed regarding overall survival (OS), although Patients with e14a2 transcript displayed a significant tendency toward a higher event free survival (EFS) ratio (P=0.03). ConclusionWe found that patients with the e14a2 transcript achieved better and faster responses to Imatinib mesylate. In this study, parallel data regarding molecular and cytogenetic responses, impact of transcript type on the probability of recurrence might suggest a general outcome that the type of transcript can be used as a prognostic marker at diagnosis.

Young CML Patients Treated Frontline with Imatinib or Second Generation TKIs: Clinical Characteristics and Outcome

Median age of CML patients at diagnosis is reported to be around 66 years. Few data about the characteristics and outcome of patients younger than 40 years are available, and the clinical trials of dasatinib and nilotinib as first line treatment were not stratified by age.We retrospectively analyzed 251 young patients with CML in chronic phase from 12 different Italian Institutions, diagnosed between October 2001 and October 2016. Up to 2011 all patients were treated frontline with imatinib while from January 2011 onwards with imatinib or a second generation TKI (nilotinib or dasatinib), based on clinical judgment. At diagnosis median age was 32,6 years [interquartile range (IQR) 27,6- 36,9]; 143 (57%) were male.Splenomegaly was found in 129 out of 233 evaluable patients, in 29,2% of the cases spleen was palpable >5 cm below the costal margin. The risk score was low in most of the cases (low risk Sokal 71%, low risk Eutos 91,3% vs high risk Sokal 9,8%, high risk Eutos 8,7%). Clinical features of the patients in treatment with different inhibitors are summarized in table 1. There were two main statistically significant differences in the group of patients treated with dasatinib: a higher proportion of high risk (30,8%) according to Eutos score and a lower median Hb level at diagnosis (8,5 gr/dL). These features probably reflected the trend of using dasatinib in patients with a more aggressive disease, as this drug was shown to be more potent since the first in vitro studies.Out of 251 patients 179 were treated with imatinib, 57 (22%) with nilotinib, 15 (5,9%) with dasatinib.Median follow up of the whole cohort was 76,5 months (IQR 41- 116); as expected, the follow up was longer in the imatinib group compared to the nilotinib and dasatinib groups (100 months vs 39,6 and 23,0 respectively).In the whole cohort, the cumulative incidence of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMolR) were 90,4% and 75,7% respectively; a deep molecular response (negative nested PCR, MR4.0, MR4,5) was achieved by 52.2% of patients, without differences among the 3 groups. Primary resistance occurred in 12,4% of patients, without differences among the 3 groups: secondary resistance occurred in 15.9% of patients, with a higher rate in the imatinib group (19,5%) as compared with nilotinib (7,0%) and dasatinib (6,7%) (p=0.047). Treatment discontinuation due to toxicity was observed in 6.0% of patients, without differences among the 3 groups. Blast transformation occurred in 7 out of 251 patients (2,8%), all in the imatinib group, after a median time from the diagnosis of 31 months (range 4-110). The 4-year cumulative Event-Free Survival (EFS) and Overall Survival (OS) were 72,4% (95%CI 66,7 - 78,5) and 98,1% (95%CI 96,4 - 99,8) respectively, without differences among the 3 groups. All deaths were related to blast transformation in imatinib group.In conclusion, as expected in a younger population, response to treatment and OS were excellent. However, the 4-year EFS was lower than expected, in spite of the presence of patients with predominantly low risk score. Furthermore, while the higher rate of secondary resistance in the imatinib group probably reflects the longer follow-up, it is worth of note that no statistically significant difference was observed between imatinib and 2nd generation TKI groups in terms of OS and EFS. [Display omitted] [Display omitted] DisclosuresBreccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

Impact of Additional Cytogenetic Abnormalities and Variant t(9;22) at Diagnosis on Prognosis of Childhood Chronic Myelogenous Leukemia : The Experience of the International Registry for CML in Children and Adolescents (I-CML-Ped Study)

▪Introduction. Chronic myeloid leukemia(CML) is a very rare disease in children and adolescents. The international registry of CML in children and adolescents gives us the opportunity to assess the prognostic relevance of variant t(9 ;22) and additional cytogenetic abnormalities at diagnosis on prognosis.Patients and Methods. We used clinical and biological characteristics and outcome of 239 children and adolescents less than 18 years to assess the impact of additional cytogenetic abnormalities and variant t(9 ;22) on the rate and the time to achieve a complete cytogenetic response (CCyR). Cytogenetic analysis was performed 24 or 48 hour culture on G-banded metaphases.Results. Overall, 17/239 children (7.1%) presented with additional cytogenetic finding at diagnosis: 5/239 children (2.1%) had a variant of the t(9;22), 10 children (4.2%) had other additional cytogenetic (numerical/structural) abnormalities (ACA), and 2/239 (0.8%) had both. Characteristics of the patients and phase of the disease are reported in Table 1. In the 7 patients with variant t(9;22), one (chromosome 1 in 3 patients, chromosome 8 in 2 patients and chromosome 14 in one patient) or two further chromosomes (chromosomes 8 and 17) were involved in 6 and one patient(s), respectively. In the 12 patients with ACA, 9 patients have one type of ACA, 2 patients have 2 type of ACA and one patient have 3 type of ACA. Regarding the patients in chronic phase at diagnosis (n=219), the cumulative incidence of complete cytogenetic response at 18 months was 88% (95% CI: 82 % - 93%) and 70% (95% CI: 42% - 93%) for patients without variant t(9;22) or ACA and for those with variant t(9;22) and/or ACA (p=0.151), respectively. Three deaths were recorded (among them one patient had ACA at initial diagnosis). With a median follow up of 43 months (range 1 – 161) the probability of 3 years overall survival was 99% (95% CI: 94 % - 100%) and 88% (95% CI: 39 % - 98%) for patients in chronic phase without variant t(9;22) or ACA and for those with variant t(9;22) and/or ACA (p=0.042), respectively.Conclusion. Additional chromosomal abnormalities at diagnosis in children with CML in chronic phase may have an impact on the outcome. A larger cohort of patient and a longer follow up is needed to confirm such findings.Table 1CytogeneticNo variant t(9;22) or ACAVariant t(9;22)ACAVariant t(9;22) and ACANumber of patients2225102Sex (% males)56%60%50%100%Median age, yrs (range)12 (1-18)14 (9-17)12 (5-16)6 and 17Phase of the disease (n)chronicacceleratedblastic208 12 23 1 17 1 21 0 1Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company DisclosuresNo relevant conflicts of interest to declare.

Correlation of Lymphocyte Count with Treatment Response to Tyrosine Kinase Inhibitors in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

▪Background:Total lymphocyte count (TLC) has been shown to correlate with outcomes in patients (pts) with acute leukemia. The clinical correlation to TLC in pts with chronic myeloid leukemia in chronic phase (CML-CP) who were treated with a tyrosine-kinase inhibitor (TKI) is unclear.Methods:Lymphocyte data in pts with newly diagnosed CML-CP who were enrolled in consecutive or parallel clinical trials with front-line imatinib (IM), nilotinib (Nilo), or dasatinib (Dasa) were collected at the time of diagnosis, and 3 and 6 months (M) after the start of TKI. Relative lymphocytrosis (RLC) was defined as lymphocyte >150% at 3 or 6M compared with baseline at diagnosis. Absolute lymphocytosis (ALC) was defined as lymphocyte > 4,000 /µL at 3 or 6M after the start of TKI. Pts were assessed for response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) based on ALC and RLC. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test and Cox regression were used for univariate (UVA) and multivariate analysis (MVA), respectively.Results:A total of 483 pts were enrolled in this study: 271 in IM, 105 in Nilo, and 107 in Dasa. Patient characteristics and outcomes are summarized in Table 1. Median age at diagnosis was 48 years, and median follow-up was 85M and ongoing (5-154+). Time from diagnosis to start of TKI, Sokal risk score, and ALC at baseline between groups did not differ clinically. Of 481 pts, 93 (19%) developed RLC at 3 or 6M; IM, 38 (14%); Nilo, 23 (22%); Dasa, 32 (30%) (p= .001). ALC at 3 or 6M was observed in 15 (3%); IM, 3 (1%); Nilo, 1 (1%); Dasa, 11 (10%) (p<.001). Overall, cumulative incidence of complete cytogenetic response (CCyR) at 6M, major molecular response (MMR) at 12M, molecular response with 4.5 log reduction by IS (MR4.5) at 24M did not differ significantly between RLC and non-RLC (3 or 6M), or between ALC and non-ALC (3 or 6M). 5-y TFS, EFS and OS in ALC group were significantly worse than those in non-ALC group (p= .002, p=.016, p=.008, respectively). By UVA and MVA related to OS, age [p <.001; Hazard ratio (HR), 1.062; 95% confidence interval (95%CI), 1.036-1.089], presence of ALC at 3 or 6M [p = .028; HR, 10.948; 95%CI, 1.297-92.415], absence of MMR at 24M [p=.016; HR, 2.263; 95%CI, 1.165-4.393] were identified as adverse prognostic factors for OS.Conclusion:The presence of ALC ≥4,000/µL at 3 or 6M of TKI therapies is rare but is adversely associated with overall survival.Table 1Patient Characteristics and Outcomes (N=483)aOverall [n= 481]IM [n= 271]Nilo [n= 105]Dasa [n= 107]Age, (year)48 (15-85)48 (15-85)49 (17-82)48 (16-83)Sokal Risk, No. (%)Low334 (69)175 (65)79 (75)80 (75)Intermediate114 (24)74 (27)18 (17)22 (21)High32 (7)20 (7)8 (8)4 (4)Time from diagnosis to start of TKI, (M)0.9 (0-12.6)1.0 (0-12.6)0.5 (0-5.6)0.7 (0.1-7.8)ALC at baseline, (/109L)2.5 (0-86.6)2.4 (0-16.7)2.6 (0.4-9.2)2.7 (0.3-86.6)Incidence of Relative Lymphocytosis, No. (%)At 3M65 (14)25 (9)16 (15)24 (22)At 6M76 (16)32 (12)20 (19)24 (22)Overall93 (19)38 (14)23 (22)32 (30)Incidence of Absolute Lymphocytosis, No. (%)At 3M8 (2)1 (0)07 (7)At 6M11 (2)3 (1)1 (1)7 (7)Overall15 (3)3 (1)1 (1)11 (10)Outcomes of RLC and ALC at any time in each group, +/- (%/%) (p)<10% BCR-ABL/ABL at 3MRLC36/40 (.596)22/44 (.213)50/37 (.280)31/38 (.537)ALC38/39 (.952)0/42 (.394)100/39 (.214)36/35 (.952)Cumulative CCyR at 6MRLC75/75 (.288)50/66 (.063)96/90 (.413)90/87 (.628)ALC67/75 (.711)33/64 (.276)0/92 (.001)82/89 (.599)Cumulative MMR at 12MRLC67/74 (.406)53/70 (.030)83/82 (.921)72/74 (.903)ALC60/73 (.488)33/68 (.197)0/83 (.033)73/74 (.745)Cumulative MR4.5 at 24MRLC46/52 (.564)37/50 (.139)57/55 (.889)50/57 (.729)ALC33/52 (.332)33/48 (.610)0/56 (.264)36/57 (.252)5-y FFSRLC61/71 (.133)56/69 (.167)62/70 (.710)61/74 (.285)ALC50/69 (.076)0/68 (<.001)0/70 (<.001)71/70 (.974)5-y TFSRLC90/93 (.369)88/93 (.597)91/88 (.115)91/99 (.213)ALC72/93 (.002)67/93 (.014)0/90 (<.001)80/97 (.121)5-y EFSRLC80/86 (.213)71/83 (.154)84/87 (.450)86/93 (.486)ALC64/85 (.016)33/82 (<.001)0/87 (<.001)80/92 (.574)5-y OSRLC89/93 (.068)81/94 (.007)100/84 (.126)96/99 (.207)ALC82/93 (.008)67/93 (.001)100/88 (.847)83/99 (.040)a Two in IM and 1 in Dasa were not evaluable due to lack of differential data at 3 and 6M. [Display omitted] DisclosuresO’Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

EUTOS score predicts survival and cytogenetic response in patients with chronic phase chronic myeloid leukemia treated with first-line imatinib

Sokal, Euro and newly developed EUTOS scoring systems were validated in 220 Chinese chronic phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib. In the EUTOS low-risk and high-risk groups, the 5-year OS was 98.7% vs. 71.4% (P<0.0001), and the 5-year cumulative incidence of complete cytogenetic response (CCyR) was 92.4% vs. 53.8% (P<0.0001). EUTOS score also predicted progression-free survival and duration of CCyR. Low EUTOS index predicted for CCyR. However, Sokal and Euro scores mainly could not discriminate the intermediate-risk from high-risk group in either survival or CCyR. EUTOS score forecasts the prognosis of CP-CML patients treated with first-line imatinib.

European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients

The Sokal and Hasford scores were developed in the chemotherapy and interferon era and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, a new European Treatment and Outcome Study (EUTOS) scoring system was developed. We performed a multicenter retrospective study to validate the effectiveness of each of the three scoring systems. The study cohort included 145 patients diagnosed with CML in chronic phase who were treated with imatinib. In the EUTOS low- and high-risk groups, the cumulative incidence of complete cytogenetic response (CCyR) at 18 months was 86.9% and 87.5% (P = 0.797) and the 5-year overall survival rate was 92.6% and 93.3% (P = 0.871), respectively. The cumulative incidence of CCyR at 12 months, 5-year event-free survival and 5-year progression-free survival were not predicted using the EUTOS scoring system. However, there were significant differences in both the Sokal score and Hasford score risk groups. In our retrospective validation study, the EUTOS score did not predict the prognosis of patients with CML in chronic phase treated with imatinib.

Frontline Treatment With Imatinib Mesylate in Chronic Myeloid Leukemia Patients in Early Chronic Phase: a Very Long-Term Analysis by the GIMEMA CML Working Party

BackgroundThe chronic myeloid leukemia (CML) therapeutic scenario has been enriched by the approval of second generation TKIs as frontline treatment of early chronic phase (ECP) patients, but imatinib mesylate (IM) still represents the standard for many patients. The long term outcome is extremely important to assess the treatment efficacy and to decide on the allocation of resources. The phase 3 trials comparing second generation TKIs versus standard-dose IM have not still demonstrated a clear improvement in terms of progression-free survival and overall survival. In the IRIS trial, at 8 year, 55% of patients were still on IM and the overall survival (OS) was 85%. Other published reports have shorter follow-up. Aims and MethodsTo assess the very long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 multicentric prospective studies conducted by the GIMEMA CML Working Party (NCT00514488, NCT00510926, observational trial CML023). Definitions: major molecular response (MMR), BCR-ABLIS ratio <0.1%; deep molecular response (MR4.0), detectable disease ≤ 0.01% BCR-ABLIS or undetectable disease with ≥10,000 ABL transcripts; progression, transformation to accelerated or blastic phase; failure, according to 2013 ELN criteria; event, treatment discontinuation for any reason or lost to follow-up. Information on survival and progression were regularly collected. All deaths, at any time and for any reason, were included. All the analysis have been made according to the intention-to-treat principle. ResultsBaseline demographics characteristics: median age: 52 years (extremes 18-84 years); male sex: 60%; high Sokal, high Euro and high EUTOS scores: 22%, 7% and 7%, respectively; clonal chromosomal abnormalities (CCA) in Ph+ cells: 4% (not evaluable in 32% of patients for insufficient number of metaphases); e13a2 BCR-ABL transcript: 36%. Median follow-up: 76 (7-99) months. The cumulative incidence of complete cytogenetic response (CCyR), MMR and MR4 was 88%, 85% and 61%, respectively. The median time to CCyR, MMR and MR4 was 6, 7 and 42 months, respectively. Patients with high Sokal, high Euro and high EUTOS scores had significantly lower overall estimated probability of CCyR and MMR with respect to low and intermediate risk patients. A high Sokal score also predicted a significantly inferior probability of MR4; patients with high Euro and high EUTOS score had lower overall estimated probability of MR4, but the difference were not statistically significant. The reasons for IM discontinuation were: lack of efficacy (19%), toxicity or death (9%), withdrawal of informed consent (3%); 4% of patients were lost to follow-up. The 8-year event-free survival (EFS), failure-free survival (FFS), progression-free survival (PFS) and OS were 55% (95% CI: 51-60%), 66% (95% CI: 61-70%), 84% (95% CI: 78-89%) and 85% (95% CI: 79-90%), respectively. A high Sokal and a high Euro scores were able to identify patients with significantly lower probability of EFS, FFS, PFS and OS with respect to the other patients. High EUTOS score patients had significantly poorer EFS and FFS, but PFS and OS differences were not significant. Age, performance status and e13a2 transcript resulted independent prognostic factors on PFS and OS. ConclusionsUntil now, the available data on the very long-term outcome of newly diagnosed chronic phase CML patients treated frontline with imatinib are limited to a company sponsored study (IRIS study). The GIMEMA CML Working Party provided an unbiased overview of the long-term imatinib therapeutic effects in a multicentric nationwide experience. These results should be taken into consideration to make treatment decision concerning the choice of the first line TKI, particularly in low risk patients. AcknowledgmentsUniversity of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. [Display omitted] Disclosures:Castagnetti:Novartis Farma: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:BMS, Novartis: Consultancy. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Cytogenetic and Molecular Responses At 3 Months Are Associated with A Better Outcome in Early Chronic Phase (ECP) Chronic Myeloid Leukemia (CML) Patients Treated with Nilotinib.

Abstract 2797 Background: Nilotinib is a second-generation tyrosine kinase inhibitor that demonstrated higher and faster responses and lower progression rates compared to imatinib in ECP CML patients. Early cytogenetic and molecular responses have been associated with a better outcome in patients treated with imatinib, dasatinib, or nilotinib frontline. In particular, BCR-ABL transcript level 4.5 (>4.5 log reduction in BCR-ABL transcript level) with dasatinib (Marin D et al, Blood 2012); increased CCyR rate by 1 year, MMR rate by 2 years, and better progression-free survival (PFS) at 2 years, with dasatinib (DASISION; Hochhaus A et al, ASH 2011, abs. 2767); increased MMR rate by 1 year, and better PFS and overall survival (OS), with nilotinib (ENESTnd; Hochhaus A et al, EHA 2012, abs. 584). Here we report a landmark analyses based on BCR-ABL transcript level and cytogenetic response at 3 months to evaluate their impact on subsequent response and outcome in an independent cohort of patients treated with nilotinib-based regimens in Italy (CML Italian Registry of Nilotinib). Methods: The CML Italian Registry of Nilotinib includes 215 patients, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Dpt. of Hematology and Oncology, Bologna University Hospital, with nilotinib 300 mg BID or 400 mg BID as initial treatment. The median age was 53 years (range 18–86). The median follow-up was 29 months (range: 18–47 months). At 3 months 196/215 (91%) and 189/215 (88%) patients were evaluable for the molecular and cytogenetic response, respectively. BCR-ABL transcript levels were: 2 1% in 88%; > 1% to 2 10% in 11%; > 10% in 1%; given the very low proportion of patients with a BCR-ABL > 10% (n. 2), to the purpose of these analyses, patients have been divided into 2 groups, with a transcript level 2 1% (n. 173, 88%), or > 1% (n. 23, 12%). Cytogenetic response was: CCyR 84%; partial cytogenetic response (PCyR) 9%; less than PCyR 7%. We analyzed the rate of MMR at 1 year, and the failure-free survival (FFS, according to ELN 2009 definitions), PFS (transformation to accelerated or blastic phase), and OS (any death included) according to the BCR-ABL transcript levels and to the cytogenetic response at 3 months. Results: Of the 2 patients with a BCR-ABL transcript level > 10% at 3 months, 1 progressed to blastic phase at 1 year, while the other one obtained a CCyR at 6 months and a MMR at 24 months. Patients with BCR-ABL 2 1% at 3 months had a higher rate of MMR at 12 months with respect to those with a transcript level > 1% (79% vs. 35%, p 2 1%) at 3 months correlated with a better FFS and PFS and a similar OS at 3 years. Patients with a MCgR and CCyR at 3 months had higher rates of MMR at 12 months (77% and 79%, respectively) vs. patients with less than a MCyR or less than a CCyR (46% and 57%, respectively) (p=0.02 and 0.019, respectively). Patients in MCgR at 3 months had a better FFS and PFS, but similar OS with respect to patients not in MCgR. Conclusion: In our national experience, where 42 centers are represented with at least 1 patient, a very small proportion of patients treated frontline with nilotinib failed to achieve a reduction to . The cut-off of 1% of BCR-ABL at 3 months in our experience is a reliable surrogate marker of response at 1 year (MMR) and outcome (PFS and FFS), along with the level of cytogenetic response achieved. These patients with > 1% of BCR-ABL at 3 months are characterized by a higher propensity to fail the treatment and to progress. Consequently, they deserve a close monitoring and, for those not achieving the expected cytogenetic and molecular responses later on (at 6–12 months), an optimization of the dose of nilotinib or a treatment modification is advised. Acknowledgments: European LeukemiaNet, University of Bologna, BolognAIL, COFIN. Disclosures: Gugliotta: Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Castagnetti: Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia: Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Abruzzese: Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Soverini: Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau. Baccarani: ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti: Novartis Pharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

Long‐term safety and efficacy of imatinib mesylate (Gleevec®) in elderly patients with chronic phase chronic myelogenous leukemia: Results of the AFR04 study

Data from registries suggest that the median age of chronic myelogenous leukemia (CML) patients is 10-15 years older than that of clinical trials. We conducted a prospective phase II study to evaluate imatinib mesylate (IM, 400 mg daily) in newly diagnosed chronic phase CML (CP-CML) patients. Patients aged 70 years and over diagnosed with CP-CML within 12 months were eligible. Thirty patients were enrolled from April 2002 to October 2004. Median age was 74.8 years (range, 70-90). Male/female ratio was 1.72. At inclusion, comorbidities were reported in all but one patient, Cumulative Illness Rating Scale for Geriatrics comorbidity mean index was 1.47, and 66% of patients had cardiovascular disease. The median daily IM dose was 392 mg (range, 256-445). IM was interrupted in patients with severe comorbidities. Treatment discontinuation was observed in 36.6% of patients. Cumulative incidence of complete cytogenetic response was 71.4 and 78.5% at 12 and 24 months, respectively. A high level of sustained responses was observed in patients with mild or moderate comorbidities. Seven-year estimated overall survival was 80.8% (95% CI: 59.0-91.7). Two-thirds of the patients were still on long-term therapy at cut-off, and no patients had died from progression. This trial was registered at http://www.clinicaltrials.gov as # NCT00219765.

Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib

AbstractDasatinib is effective therapy for newly diagnosed patients with chronic myeloid leukemia, but not all patients respond well. We analyzed the outcome of patients treated with dasatinib as first-line therapy to identify patients who are more likely to fare poorly. The 8.6% of patients who at 3 months had a BCR-ABL1/ABL1 ratio > 10% had a significantly worse 2-year cumulative incidence of complete cytogenetic response (58.8% vs 96.6%, P < .001) and molecular responses than the remaining patients with a lower transcript levels. The predictive value of the 3-month transcript level could be improved using the dasatinib-specific transcript level cut-offs, namely, 2.2%, 0.92%, and 0.57% for complete cytogenetic response, 3 log and 4.5 log reductions in the transcript level, respectively. The study was registered at www.clinicaltrials.gov as #NCT01460693.

Assessment of BCR-ABL1 Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors

We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics. We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere. Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively). A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.

Hammersmith score application identifies chronic myeloid leukemia patients with poor prognosis before treatment with second‐generation tyrosine kinase inhibitors

In this study, we confirm the validity of the proposed Hammersmith score, which identifies three risk categories of patients and establish its strength on a large group of 128 chronic myeloid leukemia patients treated with second-generation tyrosine kinase inhibitors (TKIs) after being resistant to imatinib. Sixty-one patients were identified as good risk group, 27 patients as intermediate risk group, and 40 patients as poor risk group. The 1-year cumulative incidence of complete cytogenetic response was 73% in good risk patients, 40% in intermediate risk patients, and 22% in poor risk patients (P = 0.0001). Event-free survival at 3-year was 89% in good risk group, 70% in intermediate group, and 54% in poor risk group (P = 0.0001); the estimated 3-year progression-free survival was 95% in good risk category, 93% in intermediate risk category, and 87% in poor risk category (P=0.05). Kaplan-Meier estimated that the 3-year overall survival was 100% in good risk category, 93% in intermediate risk category, and 82% in poor risk category (P=0.04). In conclusion, some prognostic factors before starting second-generation TKIs might predict cytogenetic response and outcome. The so-called Hammersmith score was not yet validated in large series of patients: we demonstrated that this score is able to discriminate patients at high risk of failure and consequent progression before treatment with second-generation TKIs.

Hammersmith Score Is Able to Identify Chronic Myeloid Leukemia Patients with Poor Prognosis Before Treatment with Second-Generation TKIs.

AbstractAbstract 3409A score aiming at early identification of CML patients showing sensitivity to second generation TKIs was proposed by the Hammersmith group. The score was created by analizing 80 patients and was based on 3 prognostic factors: previous cytogenetic response to imatinib, Sokal risk and recurrent neutropenia during imatinib. Subsequently, the score was validated in a small series of 28 patients. Aim of our study was to confirm the validity of this score and to establish its strength on a large group of CML patients resistant to imatinib and treated with second generation TKIs. One hundred twenty-seven patients were collected from 6 different Italian hematologic centers. There were 66 males and 61 females, median age 54 years (range 25–80). Twenty-seven patients received interferon before imatinib. Thirty patients had primary resistance, whereas 97 patients received second-generation TKI after acquired resistance to imatinib. The application of Hammersmith score was possible in 118 patients with available data: 52 patients were identified as good risk, 27 patients as intermediate risk and 38 patients as poor risk. The 1-year cumulative incidence of complete cytogenetic response (CCR) was 73% in good risk patients, 40% in intermediate risk patients and 23% in poor risk patients (p=0.0001). Similarly, the cumulative incidence of major molecular response (MMR) was 52% in good risk, 28% in intermediate risk and 13% in poor risk category (p=0.001). In the evaluation of event-free survival (EFS), events were considered loss of hematologic or cytogenetic response, disease progression, death for any cause, toxicity: the estimated 2-year event-free survival (EFS) was 89% in good risk, 70% in intermediate risk and 55% in poor risk group (p=0.0001). Progression-free survival (PFS) was defined as survival without evidence of accelerated or blastic phase: the estimated 2-year PFS was 97% in good risk, 93% in intermediate risk and 87% in poor risk category (p=0.05). Kaplan Meier estimated 2-year overall survival (OS) was 100% in the good risk, 93% in the intermediate risk and 82% in the poor risk category (p=0.001). In conclusion, as suggested by Milojkovic et al, some prognostic factors before starting second generation TKIs might predict cytogenetic response and outcome. As far as we known, the so-called Hammersmith score was not yet validated in large series of patients: we demonstrated that this score was able to discriminate patients at high risk of failure and consequent progression before treatment with second generation TKIs. Disclosures:No relevant conflicts of interest to declare.

Deletions of the Derivative Chromosome 9 Do Not Influence the Response and the Outcome of Chronic Myeloid Leukemia in Early Chronic Phase Treated With Imatinib Mesylate: GIMEMA CML Working Party Analysis

Deletions of the derivative chromosome 9 [der(9)] have been associated with a poor prognosis in chronic myeloid leukemia (CML) across different treatment modalities. In the imatinib era, the prognostic impact of der(9) deletions has been evaluated mainly in patients with late chronic-phase (CP) CML, giving partially conflicting results. Few data are available in the early CP setting. For this reason, in 2006, the European LeukemiaNet recommendations still considered der(9) deletions as a candidate adverse prognostic factor and required a careful monitoring of the patient. To investigate the prognostic value of der(9) deletions in early CP CML, we performed an analysis of three prospective imatinib trials of the Italian Group for Hematological Malignancies of the Adult (GIMEMA) CML Working Party. A fluorescent in situ hybridization (FISH) analysis of bone marrow cells was performed at diagnosis; der(9) deletions were detected in 60 (12%) of 521 evaluable patients. At 60 months, the cumulative incidence of complete cytogenetic response and major molecular response-and the probability of event-free survival, failure-free survival, progression-free survival, and overall survival-in patients with and without deletions were not statistically different. Our data strongly support the notion that, when investigated by FISH, der(9) deletions are not a poor prognostic factor in patients with early CP CML treated with imatinib.

Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia

Response rates in chronic myeloid leukemia (CML) are now reported based on the cumulative incidence of a single-time best response. The study aim was to examine the significance of different response criteria for CML on imatinib therapy. In all, 276 patients with chronic phase CML on imatinib therapy were analyzed. Cytogenetic and molecular responses were coded as to single best response and response at specific intervals of treatment. The cumulative incidence of complete cytogenetic response (CGCR) with imatinib was 91%; however, the incidence of CGCR at 48 months into therapy was only 78%. Similarly, the incidence of major molecular responses (best cumulative vs landmark at 48 months) were 74% versus 62%, and of undetectable BCR-ABL transcripts 38% versus 24%. There was a strong association between achievement of major cytogenetic response (Philadelphia chromosome [Ph]-positivity <or=35%) at 6 months to 12 months and survival as well as progression-free survival (PFS). Achievement of major molecular response (vs lesser molecular response) in patients in complete cytogenetic response was not associated with significant differences in survival, but showed some association with PFS. Durable CGCR and major molecular responses (documented continuously for >or=12 months) were associated with longer PFS duration but not with survival duration differences. Of interest, major molecular responses documented at least twice were noted in 71% of patients on imatinib therapy; undetectable BCR-ABL transcripts documented at least twice were noted in 34%. Achievement and durability of CGCR and of major and complete molecular responses at landmark times predict outcome in CML, and may help in comparing the efficacy of different treatments.

High Efficacy and Particular Safety Profile of Imatinib Mesylate (Glivec®) in Elderly Patients with CML in Chronic Phase: Results of the AFR04 Prospective Study.

The reported median age of the chronic myelogenous leukaemia (CML) patients (pts) enrolled in the pivotal IRIS trial was 50y. Subgroup analysis have been already published focusing on pts over 60y with the conclusion that imatinib is efficient and well tolerated. We report here the first prospective study dedicated to imatinib in elderly pts with CML in chronic phase (CP). Patients aged 70y and over were eligible if they were diagnosed with CP CML for less than 12 months. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity index was calculated for all pts. Hydroxyurea was the only treatment accepted before inclusion. Imatinib mesylate (IM, Novartis Pharma) was administered at the dosage of 400 mg QD. Cytogenetic response was assessed for each patient every 6 months during 2 years and every year thereafter. BCR-ABL analysis were performed in reference laboratories every 3 months and results expressed according to the ENL recommendations. Thirty pts with newly diagnosed CP CML were enrolled from March 2002 to October 2004. Median age was 74.8 years (70 to 90). Sex ratio (M/F) was 1.72. Thirty percent of the pts were classified as high risk, 35% intermediate risk and 35% low risk according to the Sokal score stratification. The mean severity CIRS-G index value was 1.47. Two pts had categories at level 3 (cardiopathy and nephropathy). Interval between diagnosis and imatinib initiation was 51 days (13 to 312). Median follow up was 45 months. Grade 2 to 3 neutropenia was observed in 22% of the patients (one patient received G-CSF). Grade 2 to 3 anemia was noted in 31.8% of the pts, 86% of them received rHU-EPO with a complete resolution of anemia. The most commonly reported extra haematological toxicity was oedema (71%, only one grade 3) followed by gastrointestinal symptoms (38%). Of note, 65% of the pts had cardiovascular comorbidities. The 2 pts who presented a cardiac failure episode were those with a CIRS-G cardiac categorie at level 3. Three pts stopped IM (2 already mentioned for cardiac intolerance and one for cutaneous intolerance). The median daily dose of IM was 392 mg (256 to 445), as calculated from the patients records. A transient or permanent dosage reduction was noted in 52.3% of the patients. Cumulative incidence of complete cytogenetic response (CCR) was 71.4% and 77% at 12 and 24 months respectively. One patient lost CCR after imatinib discontinuation. The cumulative incidence of major molecular response (MMR) was 25%, 56% and 59% at months 12, 24 and 36 respectively. Among pts in MMR at month 36, 25% were in complete molecular response. There was no correlation between the CIRS-G score or index and response. Among the 3 pts who stopped the treatment, 2 had CIRS-G categories at level 3. In conclusion, the toxicity of imatinib mesylate appeared more pronounced on the red cell lineage in elderly patients that reported in younger patients. Oedema are also very common but easily treated with diuretics. We observed 2 cases of cardiac failure in this cohort of high risk patients in the 2 patients with a previous level 3 CIRS-G category, suggesting a non favourable benefit/risk ratio in patients with severe comorbidity. For all other elderly patients, a high level of sustained cytogenetic and molecular responses was observed irrespective of age.

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.