Sokal Index Research Articles

Real-World Data Analysis of the Molecular Response Kinetics within the Two First Years of the RELMC-NOVA Study in Newly Diagnosed Spanish CML-CP Patients Treated with Tirosin Kinasa Inhibitors (TKIs) in First Line

Introduction: The RELMC-Nova study analyses first line treatments in patients with chronic myeloid leukemia (CML) in chronic phase (CP) in standard clinical practice in two cohorts, before (retrospective) and after (prospective) the introduction of generic imatinib in 25 hospitals throughout Spain with special emphasis on the molecular kinetics of the initial response (studied as halving time [HT] and with logarithmic reduction [log red] between 2 times). METHODS: 311 patients were registered (171 in the retrospective cohort and 140 in the prospective cohort), all of them treated with TKIs according to standard clinical practice. Molecular Response (MR) was analyzed at 3, 6, 12, 18 and 24 months of treatment in local laboratories according to local clinical practice. HT and log red were calculated between diagnosis and molecular response at 1, 2, 3 and 6 months. RESULTS:Clinical characteristics at diagnosis: total (retrospective (R)/prospective(P)) were the following: Median age 56 years (55/61), Body mass index 24.2 (24.2/24.2), Male-Female 58%-42% (56%-44%/60%-40%), Sokal Index (L-I-H) 44%-43%-13% (50%-37%-13%/37%-51%-12%) and ELTS (L-I-H) 57%-33%-10% (63%-30%-7%/50%-37%-13%). First line TKI: Imatinib (GlivecÒ): 35% (65%/0%), generic Imatinib: 34% (0%/75%), 2nd generation (2nd G) TKIs 30.3% (35%-25%): Nilotinib 20% (22%/17%), Dasatinib 10% (13%/7%), Ponatinib 0.3% (0%/1%). In the retrospective cohort 26.3% of Low o Intermediate Sokal Index patients were treated with 2nd GTKIs versus only 18.2% in the prospective cohort. Overall response rate, total (R/P): See table 1. A statistically significance difference in major molecular response (MMR) between the retrospective and prospective cohorts was only seen at 3 months. Deep molecular response (>MR4), total (R/P): See table 1. No statistically significant differences were observed between cohorts at any time point. Overall response rate, total (Imatinib/2nd GTKIs): See table 1. A statistically significance difference in MMR between imatinib and 2nd GTKIs was only seen at 3 months. Deep molecular response (>MR4), total (Imatinib/2nd GTKIs): See table 1. No statistically significant differences were observed between cohorts at any time point. Only 1 patient (0.32%) showed progression to accelerated phase. Response kinetics: See table 1. Halving time at 3 and 6 months was lower in patients treated with 2nd GTKIs, but without statistical significance. Patients with deep molecular response at 24 months showed a lower HT being statistically significant only at 6 months. Log red: No significant differences were found between patients treated with imatinib and 2nd GTKIs, although results were initially higher in patients treated with 2nd GTKIs. Patients with a deep molecular response at 24 months showed statistically significant differences in log reduction at 3 and 6 months. CONCLUSIONS: 1. Generic imatinib has cornered 1st line treatment increasing from 65% to 75% in the retrospective and prospective cohorts respectively, relegating 2ndGTIKs to high-risk patients. 2. The responses obtained in the first months were higher and faster with the 2nd GTKIs but evened out after 12 months and remained similar at 2 years. 3. Molecular response kinetics (HT or log red) can predict future response and should be assessed in patients with poor early responses. 4. A rapid decline (HR or log red) at the start of treatment guarantees a deep response at 2 years. 5. 2nd GTKIs produce faster molecular response kinetics but final outcomes were similar to that obtained with imatinib. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-Life Use of Nilotinib for Chronic Phase CML Demonstrates Similar Efficacy and Rate of Cardiovascular Events As Enestnd

Introduction:Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) widely used for the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML). ENESTnd, which compared two doses of nilotinib to imatinib for patients with newly diagnosed CML, demonstrated superior rates of major molecular responses (MMRs) at 12 months in patients treated with nilotinib. However, a relative increase in cardiovascular events (CVE) was observed, including ischemic heart disease, stroke, and/or peripheral artery disease among nilotinib-treated patients. Notably, at a median 5-year follow up, 7.5% of patients on nilotinib 300mg twice daily experienced a CVE (Hochaus, Leukemia, 2016) and by 10-years of follow up, approximately 20% of patients treated with nilotinib developed a CVE (Kantarjian, Leukemia, 2021). The baseline Framingham general cardiovascular risk scores and total dose exposure were predictive of patients' risk of developing CVE.In the province of Quebec, Canada, the GQR LMC-NMP (Groupe Québécois de recherche en leucémie myéloide chronique et néoplasie myéloproliférative) has maintained a registry of nearly all patients with CML since 2011. Using this 900+-patient registry, we examined molecular responses and the rate of CVE among patients receiving nilotinib as frontline therapy for CML, to determine if they were similar to those observed in ENESTnd.Methods:We identified all patients with chronic phase CML in the registry who were initiated on nilotinib for chronic phase CML. Baseline patient characteristics included were age, sex, Sokal index, baseline comorbidities, molecular response, cardiovascular complications, duration of exposure to nilotinib, dose adjustment, dose discontinuation and CVE on therapy.Results:In total, 94 patients received nilotinib as frontline treatment starting in 2008 (Table 1). The median age of the population was 58 years, 50.5% were male. The most common cardiovascular comorbidity prior to nilotinib treatment was hypertension (23.4%) followed by elevated cholesterol (21.3%), and prior CVE (12%). Seventeen patients had a low Sokal index, 26 intermediate and 24 high, 25 missing. Sixty-five patients received nilotinib at a total of 600 mg per day, 29 patients had a dose reduction at some point in their treatment and 18 patients were on either 300 or 400 mg daily. The median follow-up time was 67.0 months (range 0.5 to 159), and median nilotinib exposure time was 38.5 months (range 0.5 to 144). Forty-six patients (48.9%) discontinued nilotinib, 6 for a treatment free remission (TFR). While on nilotinib, 63 patients achieved MMR (72.4%) and 43 achieved MR 4.5 (49.6%) by 5 years of treatment, with 52 (55.3%) and 22 (23.4%) patients achieving MMR or MMR4.5 within a year, respectively.There was a total of 7 CVE in 6 patients: six myocardial infarctions and one ischemic stroke (Table 2). No patients developed peripheral artery disease. The mean time of exposure to nilotinib in these 6 patients was 28.6 months. Two patients had a high Sokal index, 3 intermediate and 1 low. One patient received dose-reduced nilotinib. These patients were co-morbid with diabetes (3), hypertension (3), elevated cholesterol (1) and one had a myocardial infarct prior to starting nilotinib, two patients did not have any risk factors. Only one of these patients has remained on nilotinib. All patients with a CVE were alive at the time of this report.Conclusion:We present real world data on the efficacy and safety of nilotinib in the frontline treatment of CML. Our data indicate that molecular responses and toxicities are similar to the ENESTnd trial. Of the 94 treated patients, the rate of MMR and CVE were 72% and 7.4% at 5.5 years of follow up, respectively, which is similar to that observed in ENESTnd, where 77% of patients experienced MMR and 7.5% CVE at this timepoint (Hochaus, Leukemia, 2016). All but one patient with a CVE in our study continued nilotinib, suggesting a reluctance among physicians to continue in the face of CVE. While there were 11 patients with prior CVE, only one of these developed a CVE on nilotinib. Current GQR-LMC CML management guidelines recommend estimation of Framingham score and management of cardiovascular risk factors for all patients with CML. Future follow up of these registry data may demonstrate a decrease in the rate of CVE among nilotinib treated patients, reflecting local adherence to these guidelines. [Display omitted] DisclosuresBusque: Novartis: Consultancy. Assouline: Eli Lilly: Research Funding; Jewish General Hospital, Montreal, Quebec: Current Employment; Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Johnson&Johnson: Current equity holder in publicly-traded company; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Efficacy and Safety of Generic Dasatinib As First-Line Treatment in Patients with Chronic Myeloid Leukemia in Chronic Phase: Final Analysis with 2-Year Follow-up

Purpose: Generic dasatinib, a second-generation tyrosine kinase inhibitor (TKI), was approved as a second-line treatment for chronic myeloid leukemia (CML) patients in chronic phase (CP) in china. We initiated a prospective, multi-center and single-arm clinical trial (NCT04925141) from May 2016 to October 2018 to evaluate efficacy and safety of generic dasatinib as first-line treatment in China. The primary endpoint was achieved, here we reported the 2 years follow-up results to see its long-term clinical benefit in Chinese patients.Methods:The study included the newly diagnosed CML-CP patients who was diagnosed by the presence of Philadelphia (Ph) chromosome and/or presence of BCR-ABL fusion gene. Key inclusion criteria were as follows: 1) Age ≥ 18 years; 2) The CML subjects in chronic phase with the Ph+ definitive diagnosis were within 6 months before the onset of administration of the study drug; 3) The ECOG performance grades of 0-2; 4) Sufficient main organ functions. All newly diagnosed patients were given 100mg/d (initial dose) of the generic dasatinib. The primary endpoint was molecular major response (MMR) calculated based on the BCR-ABL1 ≤ 0.1% at the 12th month. Secondary endpoints were proportion of subjects who achieved and maintained MMR at 3, 6, and 18 months; Cumulative MMR rates at 6, 12, and 24 months were determined. All patients were followed up through the hospital outpatient departments at second, fourth and eighth weeks, and third, sixth, ninth, twelfth, eighteenth, and twenty-fourth months. The follow-up ended on December 6, 2019. The SAS 9.2 software was utilized for all statistical analyses in this study, and the two-sided test was performed to see variances.Results: A total of 59 patients were included in this trail, with median age of 44 (19 - 70), and 7% of the subjects were at high risk based on the Sokal index for the disease prognosis. The primary endpoint MMR rate at the 12th month was 80.8% which had been published. At 12 months, the cumulative response rate (CCyR) was 85.5% (47/55) and the cumulative MMR was 76.4% (42/55). Here we are reporting the 2 years follow ups. At 24 months, the complete hematological response (CHR) was 88.4%, the cumulative MMR rate was 73.7%, the cumulative MR4.0 rate was 63.6%, the cumulative MR4.5 rate was 58.2%, and the cumulative complete molecular response (CMR) rate was 58.2%. The most common adverse events (AEs) was thrombocytopenia (42.4%) in hematology and pleural effusion (20.3%) in non-hematology, only 11.9% and 1.7% of whom were grade III~IV respectively.Conclusion: This was the first report on domestic dasatinib as the first-line treatment for CML-CP patients received a clinical benefit with 24 months in China. Safety was similar with that of the original study data. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A MULTICENTER NON-INFERIORITY STUDY OF EFFICACY AND SAFETY OF GENERIC IMATINIB IN CHRONIC MYELOID LEUKEMIA – FINAL ANALYSIS

This study aimed to evaluate efficacy and safety of generic imatinib (IM) compared to branded imatinib (Glivec) in chronic myeloid leukemia. The primary end-point was the achievement of a major molecular response (MMR) at 12 months and safety. Secondary end-points included response evaluation, overall (OS), event-free survival (EFS) progression-free survival (PFS) and toxicity. Ambispective, multicenter, observational, non-inferiority study, in newly diagnosed Brazilian patients with chronic phase CML patients treated with IM in first line. The historic cohort consisted of CML patients treated with branded IM (Glivec) from January 2010 to December 2011 and the prospective cohort was treated with generics between January 2015 and December 2018. A total of 493 cases (214 Glivec and 279 Generic) from 10 centers were enrolled, and 393 (80%) patients were eligible for analysis (Glivec = 163; Generics = 230). EFS was measured from the start of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated or blast crisis, no response or insufficient response to study therapy, after a predefined period of time or death from any cause at any time during initial therapy or permanent discontinuation of IM by adverse events. The median age was 45 and 49 years in Glivec and Generics groups, respectively (p = 0.056). Sokal score stratification in Glivec and generic groups, was respectively: low risk 50/50%; intermediate risk 49/38% and high risk 12/22% (p = 0.05). E14a2 (b3a2) frequency was 63% vs. 52% in Glivec and Generic group, respectively, and e13a2 (b2a2) 36% in both groups, e14a2+e13a2 were 1% vs. 12% (p = 0.005). There was no significant difference in gender, Eutos score and ECOG. The median time between diagnosis and treatment starting was 40 (0-169) and 28 (0-168) days (Glivec vs. Generics, respectively), p = 0.17. MMR rate at 12 months was 77/142 (54%) and 88/145 (61%) in Glivec and generics groups, respectively (p = 0.26). There were more failures in the generics group at 6 months (21% vs. 14%) (p = 0.03, respectively). There was no difference in grade 3-4 hematological and non-hematological toxicity in in the first 12 months. EFS at 24 months were higher in Glivec cohort and 76% vs. 53%, p < 0.0001, respectively), PFS and OS was not significantly different (respectively: 96% vs. 93%, p = 0.09 and 97% vs 96%, p = 0.41). The independent risk factors associated with inferior EFS were: generics use (HR = 1.78; 95%CI 1.06-2.99; p = 0.02) and High Sokal index (HR 2.25; 95%CI 1.38-3.67; p = 0.001). In the intention to treat analysis there was no significant difference in the primary end-point (MMR and safety at 12 months). The generics cohort presented more failures at 6 months compared to branded imatinib and inferior 24 month-EFS. There was no difference in the 24-month OS and PFS. The interpretation of the results should take into consideration the differences in CML management over the years.

Association of creatine kinase elevation with clinical outcomes in chronic myeloid leukemia: a retrospective cohort study

Implications of creatine kinase (CK) elevation, a frequent complication of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukemia (CML), on its key treatment outcomes (overall survival (OS) and event-free survival (EFS)), remain unknown. In this single center, retrospective study on 283 chronic phase CML patients on first-line TKI (median follow-up of 8.8 years), 71.7% patients had hyperCKemia with no difference in incidence between imatinib and second generation TKIs (SG-TKIs). In multivariable Cox regression analysis, hyperCKemia was associated with better OS and intermediate- and high-Sokal risk score with worse OS. In multivariable Cox regression for EFS, hyperCKemia and treatment with SG-TKI were associated with improved EFS while intermediate or high Sokal index and higher comorbidities showed worse EFS. Our study provides an evidence on the prognostic value of hyperCKemia in CML and informs clinicians not to change TKI based solely on laboratory elevations of CK.

Caractéristiques préthérapeutiques et évolutives des patients atteints de la leucémie myéloïde chronique à Abidjan Côte d’Ivoire

The diagnosis of chronic myeloid leukemia is based on the presence of translocation t(9,22). Additional cytogenetic abnormalities may exist at diagnosis and have prognostic value. The authors evaluated the relationship between these additional chromosomal abnormalities, clinical presentation, and therapeutic response. In a retrospective and comparative study from 2005 to 2015, at Yopougon university hospital, 51 cases of myeloid leukemia were selected, including 22 cases with additional chromosomal abnormalities. Thirteen types of additional Ph1 abnormalities were detected in one group, with a median age of 39years (13-73); a sex ratio of 1.4 and a low social class (49%). The median consultation time is 13months (2-29). Hepatomegaly (54%, P=0.05); fever (81.8%, P=0.0017); bone pain (63.6%, P=0.0001); lymphadenopathies (27.3% P=0.014); poor general condition [WHO>1 (77.3%, P=0.001)], high Sokal index (63.6%, P=0.0019), eosinophilia>5% (72.7, P=0.02) and circulating blastosis were found more frequent in the group with additional abnormalities treated with imatinib mesylate. We obtained 13.6% hematologic remission and 22.7% cytogenetic remission (P=0.02). The average survival was relatively short (20months vs. 76.4months, Log-rank<0.0001). We deplored a high death rate (59.1%). The presence of an additional anomaly constitutes a pejorative element refractory to imatinib.

Crosstalk between BCR-ABL and protease-activated receptor 1 (PAR1) suggests a novel target in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which generates the oncogene BCR-ABL1. Protease-activated receptor 1 (PAR1) is involved in tumor progression and angiogenesis. We have previously reported that PAR1 expression is elevated in human leukemias that display a more aggressive clinical behavior, including the blast crisis of CML. In this study, we analyzed the crosstalk between the oncoprotein BCR-ABL and PAR1 in CML. Leukemic cell lines transfected with the BCR-ABL1 oncogene showed significantly higher expression levels of PAR1 compared with that of wild-type counterparts. This phenomenon was reversed by treatment with tyrosine kinase inhibitors (TKIs). Conversely, treatment with the PAR1 antagonist SCH79797 inhibited BCR-ABL expression. The PAR1 antagonist induced apoptosis in a dose- and time-dependent manner. Higher vascular endothelial growth factor (VEGF) levels were observed in cells transfected with BCR-ABL1 than in their wild-type counterparts. VEGF expression was strongly inhibited after treatment with either TKIs or the PAR1 antagonist. Finally, we evaluated PAR1 expression in CML patients who were either in the blast or chronic phases and had either received TKI treatment or no treatment. A significant decrease in PAR1 expression was observed in treatment-responsive patients, as opposed to a significant increase in PAR1 expression levels in treatment-resistant patients. Patients classified as high risk according to the Sokal index showed higher PAR1 expression levels. Our results demonstrate the crosstalk between BCR-ABL and PAR1. These data may offer important insight into the development of new therapeutic strategies for CML.

Performance of Sokal and Eutos Scores for Predicting Cytogenetic and Molecular Response in Newly Diagnosed Chronic Myeloid Leukemia-Chronic Phase Patients on Imatinib

Sokal index was developed in the pre-imatinib era to predict and prognosticate the outcome of Chronic myeloid leukemia (CML) patients. In the Imatinib era, a new scoring system called EUTOS scoring system has been validated as a predictive marker in CML. The scores have shown variable correlation with complete cytogenetic response (CCyR) and major molecular response (MMR). To assess the performance of Sokal score and EUTOS score as a predictive marker for CCyR and MMR for newly diagnosed CML-CP patients treated with TKIs. 273 patients with newly diagnosed CML were included in the study. They were treated with upfront imatinib. They were followed up for a median period of 3years. Cytogenetic and Molecular response to the treatment were monitored regularly. Out of 273 patients, 174 patients (63%) were having low EUTOS score and 99 (37%) were having high EUTOS score. Patients with low, intermediate and high sokal scores were 237 (86.8%), 28 (10.3%) and 8 (2.9%) respectively. 122 patients with low EUTOS score achieved CCyR within 18months compared to 42 patients with high EUTOS score (p=0.000).113 patients with low EUTOS score achieved MMR in 18months compared to 33 patients with high EUTOS score (p=0.000). 148, 14, 2 patients with low, intermediate and high Sokal score respectively have achieved CCyR in 18months (p=0.054). 133, 11, 2 patients with low intermediate and high sokal score respectively have achieved MMR in 18months.(p=0.06). EUTOS is better than Sokal score in predicting the outcome of patients of CML treated with imatinib.

Chronic Myeloid Leukemia (CML): BCR-ABL Transcript Levels Halving Time and Relative Reduction Ratio at Months 3 As New Predictors of Outcome. an Argentine Pilot Study

▪BCR-ABL transcript levels (IS%BCR-ABL) in CML patients (pts) allow to define molecular response (MR) to TKIs. MR at 3 months (M3>10%) is the strongest predictor of bad outcome and a point of divergence for changing therapy. Emerging biomarkers are being proposed in order to optimize prognosis in addition to initial MR and other clinical markers. The rate of BCR-ABL decline measured as halving time (HT) for transcript level reduction (RT0.5) at month 3 in 1GTKI (imatinib) treated pts, and the fractional clearance as a relative BCR-ABL ratio (RR3) during the first 3 months in 2GTKI (dasatinib) treated pts were recently proposed as predictive markers of outcome. Optimal responses (OR) were defined upon %ISBCR-ABL values at 3, 6 and 12 months: M3 ≤10%, M6 ≤1% y M12 ≤0,1%. Early time point prognostication could allow better outcome predictions and rapid therapeutic interventions.Aim: to determine whether the rate of BCR-ABL decline as HT and the BCR-ABL transcripts reduction as relative ratio at M3 from baseline, have predictive value in CML pts treated with 2GTKIs.Method: BCR-ABL transcript level was measured by Q-PCR according international recommendations and results were reported as BCR-ABL/ABL on the international scale (IS BCR-ABL %). Molecular monitoring was performed prior treatment (M0) and at months 3 (M3), 6 (M6), 12 (M12) and every 6 months thereafter. RT0.5 from baseline to M3 was calculated as the time to halve by considering an exponential model of reduction during the period. The median RT0.5 and quartiles, were calculated to define rapid declines as those HT in the lowest quartile. RR3 was determined as a relative ratio of transcript clearance at M3 from baseline. The median RR3and quartiles, were considered to define high BCR-ABL clearance as those in the highest quartile. Fisher statistical test was used to determine whether the proportions of good responses were statistically different depending on the decline rate.Results: A total of 77 CML pts were included, first line treatment: Dasatinib (D) 28%, Nilotinib (N) 32% and Imatinib (I) 40%. Sokal risk score was available in 70% pts: low (L) 67%, intermediate (In) 22% and high (H) 11%. Molecular assessment: prior therapy M0 (90%), M3 (60%), M6 (79%), M12 (78%) and M0+M3+M12(39%). Deep responses (MR4.0) were considered as IS%BCR-ABL<0,01 or no detectable transcripts in ≥10000 ABL copies. OR according to first line TKI (I vs D+N), were: M3≤10%: 75% vs 90% and M12 ≤0,1%: 50% vs 65%. RT0.5 median values for I vs D+N groups were 32d vs 16d and RR3 median values were 79% vs 98%. RT0.5 ≤13d and RR3 ≥99% were cut off values for fast responses and high clearance in pts treated with 2GTKI(83%). Milestone molecular result M3≤10% showed 20% pts with M12>0,1% and without MR4.0. All of these pts showed RT0.5 >13d and RR3 <99%. From total pts with OR, 80% pts achieved MR4.0 and all showed RR3≥99% meanwhile the remaining 20% pts who never achieved MR4.0 had RR3<99%. Higher frequencies of OR were observed in low Sokal risk pts, in RT0.5 ≤13d pts and in pts with RR3 ≥99%. High Sokal risk pts had poorer results at milestones molecular responses but those with rapid initial decline (RT0.5 ≤13d) and high BCR-ABL clearance (RR3 ≥99%) achieved molecular responses similar to those observed in the low risk sokal group.Conclusions: Faster BCR-ABL decline and high clearance were related to OR and MR4.0 achievement in 2GTKIs patients. No direct relation between Sokal Index and M12≤ 0,1% was observed. Patients with RT0.5 ≤13d showed higher frequencies of good responses. Statistical differences were not found probably due to low sample numbers. Our data suggests that RT0.5 in 2GTKIs (N+D) patients could have a similar predictive value as reported by Branford in 2014, even though it is known that BCR-ABL measurements tend to be less satisfactory when control gene is ABL, owing to possible non-linear ratios. Whilst there were no statistical correlations probably due to the low sample number, pts with OR but no MR4.0 had low reduction rate RR3<99%. RR3>99% could provide a stronger predictive value for milestone optimal responses achievement in high risk pts. It will be necessary to extend this study including a higher number of patients treated with 2G TKIs. [Display omitted] DisclosuresVarela:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pavlovsky:Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Pavlovsky:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Safety and efficacy of nilotinib after 10 years of interferon

Here we describe a case of a woman with chronic myeloid leukemia at high risk, according to the Sokal Index. The patient started interferon alfa-2b (IFN) at standard dose obtaining a major molecular response after about four years of treatment. After about 10 years the patient presented a toxicity from IFN and different comorbidities, so she was switched to nilotinib and achieved a complete molecular response (MR4). This case shows how nilotinib is effective and tolerable also in patients with multiple comorbidities. Keywords: Chronic myeloid leukemia; Optimal response; Nilotinib; Interferon alfa-2b

Major molecular response induced by nilotinib as first line treatment in a LMC patient with intermediate Sokal risk

Here we describe a case of a man with chronic myeloid leukemia at intermediate risk, according to the Sokal index. After cytoreduction with hydroxyurea, the patient started nilotinib at standard dose (600 mg/day) obtaining a complete haematological response after one month of treatment.After about 3 months the patient presented a complete cytogenetic response and after six months major molecular response (MR3). At nine months of treatment the patient presented a complete molecular response (MR4).

Different response to imatinib and nilotinib in relationship with the time of administration

Here we describe a case of a young patient with chronic myeloid leukemia at low risk, according to the Sokal index. After cytoreduction with hydroxyurea, the patient started imatinib at standard dose (400 mg/day) obtaining a minor cytogenetic response (Ph+ 42.5%) after six months of treatment.Considering the low imatinib concentration evaluated with the blood level testing, we increased the dose of imatinib at 600 mg/day. After about 3 months treatment the patient presented a partial cytogenetic response (Ph+ 30%). Therefore he was considered suboptimal responder according to European LeukemiaNet (ELN) recommendations 2006. For this reason he switched to second generation tyrosine kinase inhibitor nilotinib, at dose 800 mg/die. After switching to nilotinib the patient reached complete cytogenic response and major molecular response, maintained until last molecular evaluation.This kind of patient shows a different response for imatinib and nilotinib, whereas nilotinib therapy has shown to be safe and efficacy.

Efficacy of nilotinib in a young patient with high Sokal risk CML Ph+ in treatment failure after high dose imatinib

This article describes the case of a 44 year old man, at high-risk according to the Sokal Index, after CML Ph+ diagnosis, started imatinib at the standard dose (400 mg/day). Initially he reached optimal response, but at month 12, because of a loss of cytogenetic response, he was documented as a treatment failure. The mutational screening revealed no mutations and the blood level testing (BLT) showed values of ​​lower limits, therefore he increased imatinib to 800 mg/day. This therapeutic choice did not result in the achievement of an optimal response and the imatinib compliance was deteriorated. So, after nearly 12 months of treatment with high dose imatinib, we considered the treatment as a failure, and he switched to nilotinib, at the dose of 800 mg/day. After only 3 months of treatment, he reached complete cytogenetic response (CCyR) and major molecular response (MMolR), which the patient continues to maintain, as documented by the recent evaluation at month 30.

Chronic myeloid leukemia: successful therapy with nilotinib in a young patient with high Sokal risk and in sub-optimal response with imatinib

Here we describe a case of a young patient with chronic myeloid leukemia, at high-risk according to the Sokal index, who started imatinib at standard dose and obtained a sub-optimal response at 12 months. This condition was not automatically an indication to change therapy, but considering the patient as suboptimal, we decided to switch to a second-generation tyrosine kinase inhibitor (TKI), nilotinib 800 mg/die, obtaining soon a complete cytogenetic response (CCYR), thereafter a major molecular response (MMolR). Delayed achievement of cytogenetic and molecular is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving imatinib therapy. Therefore we can hypothesise that this kind of patient could be elegible for an early switch to second-generation TKI.

KIR2DL5B Genotype Independently Predicts Poor Outcomes in CML-CP Patients Switched to Nilotinib after Suboptimal Responses to Imatinib and May Refine Prognosis in Patients with EMR Failure

KIR2DL5B Genotype Independently Predicts Poor Outcomes in CML-CP Patients Switched to Nilotinib after Suboptimal Responses to Imatinib and May Refine Prognosis in Patients with EMR Failure

A Rare Case of Chronic Myeloid Leukemia At a Patient with Achondroplasia

The coincidence of chronic myeloid leukemia (CML) and achondroplastic dwarfism is very rare. A 40-year old man with achondroplastic dwarfism was diagnosed with chronic myeloid leukemia in blastic phase with a Sokal index of 1.34. Standart dose imatinib treatment was immediately started after the diagnosis.

Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities

AbstractEarly responses to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)-chronic phase (CP) are associated with improved outcome. We analyzed the impact of such a response on outcomes among patients treated with 4 TKI modalities as frontline therapy in CML-CP. A total of 483 patients who received 400 or 800 mg imatinib, nilotinib, or dasatinib were analyzed. The median follow-up was 72 mo. Landmark analysis at 3 mo by molecular response showed that the cumulative proportions of 3-y event-free survival (EFS) for 3-mo BCR-ABL levels was 95% for those with ≤1%, 98% for >1% to 10%, and 61% for those with >10% (P = .001). The corresponding values by cytogenetic responses were 97% if Ph+ = 0%, 89% if Ph+ = 1% to 35%, and 81% if Ph+ >35% (P = .001). Cytogenetic response at 3 mo significantly discriminated for 3-y overall survival (OS): 98%, 96%, and 92%, respectively (P = .01). In multivariate analysis, young patients, high Sokal index, and treatment with imatinib 400 significantly predicted for poor (>35%) cytogenetic response at 3 mo. Early responses are predictive for EFS and failure-free survival and to a lesser extent OS, regardless of the treatment modality, although therapies other than standard-dose imatinib result in higher rates of deep early responses. This trial was registered at www.clinicaltrials.gov as ID01-151 NCT00038649, ID01-015 NCT00048672, DM00-163 NCT00333840, ID02-534 NCT00050531, 2005-0422 NCT00254423, and 2005-0048 NCT00129740.

A comparative study of Hasford score and Sokal index in prognostication of the novo chronic myeloid leukemia patients and a search for new prognostic markers

Chronic myeloid leukemia (CML) is a common myeloproliferative disorder. Based on clinical and hematological parameters, two prognostic scoring systems, i.e., Hasford and Sokal index scoring systems are available to predict survival duration of CML patients on imatinib therapy. Our study's objective is to compare Hasford score with Sokal index for the prognostication of de novo CML patients on therapy and find out new prognostic markers. This is a retrospective study. The study population comprised 66 patients who were followed up for 60 months. For each patient, at presentation, scoring was performed as per Hasford and Sokal index and Philadelphia chromosome analysis was carried out by conventional cytogenetics. Thereafter, hematological parameters were assessed 3 monthly and conventional cytogenetics was done yearly. Out of these 66 patients, the number of patients belonging to low, intermediate and high risk categories are 21, 33 and 12 respectively by Hasford score and 12, 32 and 22 respectively by Sokal index. Eight patients, who had been categorized into high risk group by Sokal index but intermediate risk group by Hasford score, have shown better survival possibility as monitored by hematological and cytogenetic parameters. Ten cases, categorized into intermediate risk group by Sokal index but low risk group by Hasford score, is doing well till date. This study shows that Hasford score predicts survival of the patients better than Sokal index. However, multicentric study over a large population is needed to give the final verdict.

CML Patients Show Sperm Alterations At Diagnosis That Are Not Improved On Tyrosine Kinase Inhibitor Treatment

AbstractAbstract 1669Most epidemiologic studies performed in chronic myelogenous leukemia (CML) relate that the disease occurs preferentially in males with a sex ratio of ∼1.2. In addition, CML can be diagnosed in young adults and masculine fertility is a matter of concern, particularly because tyrosine kinase inhibitors (TKI) may impact on spermatogenesis by a selective inhibition of Src kinases, PDGF-R and c-kit. Sperm cryopreservation is recommended by some authors at diagnosis in males that would expect to have children later on. In a retrospective analysis we have analysed the spermograms of 62 chronic phase (CP) and 2 onset blast crisis (BC) CML males referred to our 3 centres between 2001 and 2012, collected at diagnosis before TKI treatment, and we have compared the results obtained to those of 15 healthy volunteer donors from the cryopreservation bank database, after informed consent. In 10 patients we could collect some data for patients being on imatinib mesylate (IM). CML patients had a median age of 31 (16–48) years, significantly younger than that in the control group of healthy donors: 37 (34–45) years (p=0.001). Sokal scores were 24% high, 27% intermediate and 49% low for evaluable patients (13 patients unknown or not available). The median BCR-ABLIS value at diagnosis was 77.65%. Patients had a median duration of 26 (0–38) days of hydroxyurea prior to commencing any TKI and 65% of evaluable patients had HU before TKI. None of the patients got interferon prior to TKI. The semen cryopreservation was performed within a median of 10 (2–102) days after CML diagnosis and after a median abstinence of 5 (0.5–30) days. The median volume of semen obtained in CML patients was 2.95 (0.5–14.9) ml and 3 (1.4–5.3) ml for normal donors (p=0.3). Williams test showed 72 (0–87)% of necrospermia in patients versus 18 (4–32)% in donors (p=0.00003). The median number of spermatozoa obtained was not different in patients [46 (0.03–200) 106/ml] than that in donors [74 (19.2–253) 106/ml] (p=0.24), as well as the number of spermatozoa per ejaculate observed (p=0.49). The motility of spermatozoa at 30 minutes after collection was not different between patients (median = 47.5%) and donors (median = 50%) (p=0.12), however higher numbers of atypical spermatozoa were observed in patients [median = 77.5 (16–100)%] rather than in donors [median = 45% (22–89)%], p=0.008, and the multiple abnormalities index (MAI) was significantly higher in patients [median = 1.99 (1.14–2.7)] than that in donors [median = 1.33 (1.09–1.55)], p=0.00006. There was no correlation between age at diagnosis, Sokal index and the number of spermatozoa per ml obtained (p=0.7 and 0.21 respectively).Ten CP CML patients had spermograms after a median of 1440 (9–1456) days of IM treatment and the results obtained were compared to i) the results of each individual patient at CP diagnosis and ii) to the results of healthy comparators. In comparison to the characteristics observed at diagnosis, the semen volume (median = 3.1 ml), Williams test (median = 65%), the motility at 30 minutes (median = 37.5%) and the MAI (median = 1.71) were not different (p=ns for all), however, the numbers of spermatozoa (median = 14.9 106/ml and = 37.05 ml per ejaculate) collected on IM were significantly lower (p=0.014 and p=0.045 respectively). The different parameters evaluated on IM were compared to those of normal controls and showed significant alterations. The semen volume was not different (p=0.94), neither the motility of spermatozoa (p=0.24), but the Williams test was highly perturbed on IM [median 65 (24–79)% versus 18 (4–32)% in donors] p=0.00003, as well as the numbers of spermatozoa as 106 per ml, collected on IM [median 14.9 (0.67–179)) versus normal [74 (19.2–253)], p=0.0036 or as 106 per ejaculate collected on IM [median 37.5 (2.68–572.8)) versus normal [149 (30–535.3)], p=0.026. Atypical forms were significantly more abundant on IM [median = 80 (68–90)%] versus healthy controls [median = 45% (22–89)], p=0.0058. Finally, the MAI was severely altered on IM [median = 1.71 (1.61–1.98)] versus normal individuals [median = 1.33 (1.09–1.55)], p=0.00013.In conclusion, this work demonstrates the existence of significant sperm alterations in young males with CML at diagnosis of undetermined origin, prior to any treatment. These alterations persist on IM treatment and little is know about the impact of second generation TKI. Thus the most appropriate approach remains a matter of debate in thus setting. Disclosures:Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huguet:Novartis, BMS: Speakers Bureau. Michallet:Novartis, Pfizer, Teva, Genzyme, Janssen Cilag, BMS, Merck, Pfizer, Gilead, Alexion: Consultancy, Speakers Bureau. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy.

Impact of Second-Generation Tyrosine Kinase Inhibitors As Second Line Treatment for Patients with Chronic Myeloid Leukemia,

Abstract 3780 Background:Imatinib has shown an outstanding improvement in the prognosis of chronic myeloid leukemia (CML) patients. Nevertheless, some of them have proven to be resistant or intolerant to imatinib. For these patients, second-generation tyrosine kinase inhibitors (TKIs) are available. These drugs may be indicated in different circumstances as primary or second resistance, suboptimal responses or intolerance.The real benefits of second-generation TKIs as salvage treatment are surely in dependence with the indication in each case and are, therefore, difficult to evaluate. Second-generation TKIs are being evaluated as first line treatment compared to imatinib with quite favourable outcomes so long, but have not yet been compared with a strategy combining imatinib followed by second-generation TKIs for patients with previous unfavourable responses. Aims: Evaluate the real benefit of second-generation TKIs in second line treatment for CML patients regardless of the indication for its use. Study groups and methods: We have studied 98 patients treated with imatinib as first tyrosin kinase inhibitor (TKI) in our centre. These patients have been classified according whether second-generation TKIs were available or not. Group 1 includes 60 patients treated since 2001 to 2005, when the only salvage treatment was an increased imatinib dose, chemotherapy or allogenic stem cell transplantation. Group 2 includes 38 patients treated since 2005 until today. In the second group second-generation TKIs (dasatinib or nilotinib) were used according to the indications mentioned above. Follow up period was 39 months and 32 months for group 1 and 2 respectively. Sokal risk index was high in 14% and 16%; intermediate 42 % and 40%; and low in 44% and 44 % for group 1 and 2 respectively. Results: The use of second-generation TKIs as second line resulted in significant benefit to patients in terms of responses. Complete cytogenetic responses (CCR) at any time were achieved in 73% and 86% for patients in group 1 and 2 (p=.09). Probability of the achievement of mayor molecular responses (MMR) was 42% vs 71% for group 1 and 2 respectively [p=.009; ratio=0.3 (0.1–0.7)]. Response rates at the last follow up for group 1 and 2 were: MMR: 33% vs 62%; CCR: 68% vs 94% and failure 32% vs 6% (p=.008). Progression free survival (including all the patients who started treatment) was 88% vs 94% for group 1 and 2 respectively. We found no correlation among responses and some prognostic factors (Sokal index, mutations at the TK domain or imatinib plasma levels). Imatinib doses were increased in 21 patients (35%) in group 1 (reasons for increasing doses were failure in 14 patients and suboptimal responses in 7 patients). 10 patients (26%) in group 2 received second-line TKIs as second line treatment (4 because imatinib failure, 3 by suboptimal responses and 3 due to intolerance). Conclussions: The use of second-generation TKIs as salvage has improved the responses of CML patients treated with TKIs. Once the second-generation TKIs has shown benefit compared to imatinib in first line treatment, this therapeutic strategy should be compared vs the use of imatinib followed of second-line TKIs for patients without optimal responses to imatinib. Disclosures:Montalban:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.