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e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript. [ABSTRACT FROM AUTHOR]

Background: Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors (TKIs) approved in Italy for frontline treatment of chronic‐phase chronic myeloid leukemia (CP‐CML). The choice of TKI is based on a combined evaluation of the patient's and the disease characteristics. The aim of this study was to analyze the use of frontline TKI therapy in an unselected cohort of Italian patients with CP‐CML to correlate the choice with the patient's features. Methods: A total of 1967 patients with CP‐CML diagnosed between 2012 and 2019 at 36 centers throughout Italy were retrospectively evaluated; 1089 patients (55.4%) received imatinib and 878 patients (44.6%) received a second‐generation (2G) TKI. Results: Second‐generation TKIs were chosen for most patients aged <45 years (69.2%), whereas imatinib was used in 76.7% of patients aged >65 years (p <.001). There was a predominant use of imatinib in intermediate/high European long–term survival risk patients (60.0%/66.0% vs. 49.7% in low‐risk patients) and a limited use of 2G‐TKIs in patients with comorbidities such as hypertension, diabetes, chronic obstructive pulmonary disease, previous neoplasms, ischemic heart disease, or stroke and in those with >3 concomitant drugs. We observed a greater use of imatinib (61.1%) in patients diagnosed in 2018–2019 compared to 2012–2017 (53.2%; p =.002). In multivariable analysis, factors correlated with imatinib use were age > 65 years, spleen size, the presence of comorbidities, and ≥3 concomitant medications. Conclusions: This observational study of almost 2000 cases of CML shows that imatinib is the frontline drug of choice in 55% of Italian patients with CP‐CML, with 2G‐TKIs prevalently used in younger patients and in those with no concomitant clinical conditions. Introduction of the generic formulation in 2018 seems to have fostered imatinib use. Among 1967 Italian patients diagnosed between 2012 and 2019 with chronic‐phase chronic myeloid leukemia (CP‐CML), 1089 patients (55.4%) received imatinib and 878 patients (44.6%) received a second‐generation tyrosine kinase inhibitor: nilotinib or dasatinib. Factors associated with the predominant use of imatinib were age >65 years, enlarged spleen, the presence of comorbidities (hypertension, diabetes, chronic obstructive pulmonary disease, previous neoplasms, ischemic heart disease, and stroke), and ≥3 concomitant medications at the time of CML diagnosis. [ABSTRACT FROM AUTHOR]

The outcome of chronic myeloid leukemia (CML) patients improved in the last decade. Clinical prognostic scoring systems aim to provide information about survival in the long-term, without determining from baseline the subset of patients who require a strictly monitoring because at increased risk of failure. Imatinib, the first-generation tyrosine kinase inhibitor (TKI), is still widely used as frontline treatment: recently, the imatinib therapy failure (IMTF) score was proposed to identify the failure free survival. Aim of our study was to validate this index in a large cohort of patients treated with imatinib. [ABSTRACT FROM AUTHOR]

A limited amount of data has been published in chronic-phase chronic myeloid leukemia (CP-CML) patients aged >75 years treated frontline with second-generation tyrosine kinase inhibitors. To address this issue in a clinical 'real-life' setting, we retrospectively analyzed 45 CP-CML patients (pts) followed in 20 Italian Centers and treated frontline with dasatinib (DAS). Median age was 78.4 years (range 75–89.2 years). DAS starting dose was 100 mg QD in 35 pts (77.7%), 80 mg QD in 1 pts (2.2%) and 50 mg QD in 9 pts (20.1%), respectively. The median follow-up was 42.6 months (IQR 20.4 − 63.3). Grade 3 and 4 side effects, both hematological and non-hematological, were detected in 6 (13.3%) and 12 (26.6%) pts, respectively. Pleural effusions of all grades occurred in 13 pts (28.8%) after a median period of DAS exposure of 14.7 months (IQR 3.0 − 33.1). The rates of DAS dose reduction and permanent drug discontinuation were 53.3% and 20.0%, respectively. As the best response, 42/45 patients (93.3%) achieved a complete cytogenetic response (CCyR), 35/45 (77.7%) a major molecular response (MMR) and 24/45 (53.3%) a deep molecular response (both MR 4.0 and MR 4.5). Only 1 patient (2.2%) progressed to the blast phase after 13 months of therapy; 8 deaths were observed (1 CML-related and 7 CML-unrelated). Cumulative event-free survival and overall survival at 36 months were 64.7% (95%, CI 49.4 − 80.0) and 82.3% (95%, CI 70.3–94.3), respectively. These findings, although evaluated in a limited and selected cohort of patients, suggest that DAS might be effective in older patients (aged >75 years) affected by CP-CML with acceptable toxicity. [ABSTRACT FROM AUTHOR]

We report the long-term outcome of 139 patients treated with imatinib in late chronic phase after IFN failure. Median follow-up was 16.6 years and the estimated 18-year OS was 64.8%. 18-year EFS and PFS were 69% and 64.4%, respectively. Fifty (36%) patients stopped imatinib, 72% received a second line. b2a2 transcript was associated with a significantly inferior 18-year OS (p = 0.008), FFS (p = 0.036), PFS (p = 0.013) compared to the b3a2 type, whilst the type of transcript did not influence the time to response achievement. Failure to achieve MMR at 12 months significantly reduced the chance of reaching a DMR (p = 0.001). Imatinib discontinuation after achieving a sustained deep molecular response was attempted in 14 patients; 12 (86%) are still in treatment-free remission (TFR) at the last follow-up. Our experience confirms the long-term efficacy of imatinib after IFNα failure in real-life setting and documents the possibility of attempting a TFR in this subset of patients. [ABSTRACT FROM AUTHOR]

Since July 2017, different generic imatinib formulations have been introduced in Italy for the treatment of patients with chronic myeloid leukemia (CML). We analyzed 168 chronic phase CML patients treated with branded imatinib for a median of 12 years (range 1–16) at a single institution who switched to a single generic formulation in order to assess the safety and impact on molecular response. The Sokal risk was low/intermediate/high in 63%, 33%, and 4% of patients, respectively. The median duration of generic imatinib treatment was 19 months (range 4–22). Twenty-seven percent of patients were in MMR and 73% were in deep molecular responses (MR4–4.5) at the time of the switch. After 12 months of treatment with generic imatinib, 140 patients were evaluable for response: 23.6% and 76.4% were respectively in MMR and in deep molecular response. When the degree of response was compared with the best molecular response observed with branded imatinib, it was found that 84% of patients maintained the response previously achieved, 6% improved it, and 10% of patients had a molecular fluctuation from the previous deep molecular response to MMR. Only 1 patient lost the MMR and no patient switched to another TKI for inefficacy. In terms of safety, 20% of patients reported new or worsening side effects, but only 2 patients returned to branded imatinib for toxicity. Our data show that the switch to generic imatinib in patients who have been previously treated with branded imatinib appears to maintain efficacy, although a proportion of patients experience new or worsening side effects. [ABSTRACT FROM AUTHOR]

Background: In elderly patients with chronic myeloid leukemia (CML) responsive to imatinib, the incidence of clinically significant (CS) late chronic anemia is still unknown. Materials and Methods: To highlight this issue, we revised retrospectively 81 CML patients aged >60 years treated at our Institution with front-line imatinib for at least 24 months in durable complete cytogenetic response (CCyR). CS late chronic anemia was defined as the presence of persistent (>6 months) and otherwise unexplained Hb levels ≤10 g/dL, which occurred >6 months from imatinib start. Results: A condition of CS late chronic anemia occurred in 22 out of 81 patients (27.2%) at different intervals from imatinib start. Seven out of 22 patients (31.8%) needed packed red cell transfusions during the follow-up. At diagnosis, patients who developed CS late chronic anemia were significantly older and had a lower Hb median level. Six out of 22 patients with CS late chronic anemia received subcutaneous recombinant alpha-erythropoietin (EPO) at the standard dosage of 40,000 IU weekly: all 6 patients achieved an erythroid response. A significantly worse event-free survival (EFS) in patients with untreated CS late chronic anemia was observed (p = 0.012). Conclusions: CS late chronic anemia during long-term treatment with imatinib is a common complication in responsive elderly patients, with worse EFS if untreated. Results with EPO are encouraging, but larger studies are warranted to define its role. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate differences in clinical results according to age among patients with chronic myeloid leukemia (CML). Methods: 207 consecutive CML patients treated with imatinib frontline were revised, dividing them in young adults (>20 < 45 years) (YA), middle‐aged adults (≥45 < 65 years) (MA) and elderly (≥65 years) (EL). Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

We investigated the median estimated glomerular filtration rate (eGFR) changes in chronic myeloid leukemia (CML) patients treated front line with tyrosine kinase inhibitors (TKIs). A large cohort of 397 patients-320 treated front line with imatinib, 25 with dasatinib, and 53 with nilotinib-was retrospectively analyzed at a single institution. The eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation for all patients at baseline and then at 6 and 12 months, and at the last follow-up. Taking into account eGFR changes during the first year of treatment and excluding other possible cardiovascular risk factors, we considered also the percentage of cardiovascular events in patients with modifications of this single parameter. Imatinib induced a decrease in median eGFR (p = 0.01): 42 patients treated with imatinib had a cardiovascular event, related to modification of eGFR, in the absence of other cardiovascular risk factors. In patients treated with nilotinib, the median eGFR did not decline from baseline: only 1 patient experienced an ischemic event, but the eGFR remained unchanged. In patients treated with dasatinib, the mean eGFR did not change significantly: 3 patients experienced a cardiac ischemic event, but in all patients the eGFR remained unchanged over time, while advanced age and metabolic alterations contributed to the ischemic events. This long-term follow-up has documented that imatinib may induce changes in the eGFR, which may contribute to the onset of ischemic events. Further analyses on larger series of CML patients are required to conclusively define the potential renal toxicity of second generation TKIs and the consequent risk of developing ischemic events. [ABSTRACT FROM AUTHOR]

The article presents a study that investigated if a pattern of molecular response (MR) instability could affect overall survival (OS) and failure-free survival in a series of chronic myeloid leukaemia(CP-CML) patients who received imatinib for a median follow-up of 7 years. Topics discussed include analysis of the patients for mutational screening with Sanger sequencing analysis and the association of MR3 with increased probability of developing resistance to imatinib.

Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real-life. To address the impact of this bias on the first-line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3-70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty-eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real-life management of CML patients should be regarded with caution. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents a study which aims at assessing rate of response in cohort of chronic phase chronic myeloid leukaemia (CML) patients treated with second‐generation tyrosine kinase inhibitors (TKIs). It mentions that having a higher body mass index (BMI) at diagnosis is a risk factor in terms of response achievement and time of response to treatment in CML patients treated with imatinib frontline. It states that high BMI has been observed in patients receiving nilotinib or dasatinib.

The article focuses on us effect of tyrosine kinase inhibitors (TKIs) in treatment of chronic myeloid leukemia (CML). Topics discussed include introduction of concept of operational cure by professor John Goldman related to allogeneic stem cell transplant, exploration of treatment-free remission (TFR) through several trials with imatinib and nilotinib, and patient's perspective on effects of treatment discontinuation.

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75–93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ≥ 1. Imatinib standard dose was reduced at start of therapy (200–300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ≥ 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ≥ 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ≥ 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ≥ 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ≥ 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ≥ 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ≥ 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients. [ABSTRACT FROM AUTHOR]

Abstract: Only a small fraction of chronic phase chronic myeloid leukemia patients (CP-CML) achieves a very deep reduction of residual disease with imatinib. Second-generation tyrosine kinase inhibitors administered as front-line therapy for CP-CML have improved the rates and degree of deeper molecular responses. Owing to this improvement, new standardized definition of complete molecular remission has been provided, which allowed plan of prospective strategies to definitively discontinue therapy in the long-term. In this review, we report the results of several published discontinuation studies and critically discuss the new approaches and tools to monitor residual disease during treatment and new strategies to target leukemic stem cells to reach a potential “operational” cure and persistent long-term leukemia-free survival. [Copyright &y& Elsevier]

With the advent of target therapies, imatinib became the mainstay for treatment of chronic myeloid leukemia. However, despite the brilliant results obtained with this drug, more than 30% of patients discontinue therapy in long-term due to several reasons, including failure and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) are more potent drugs and have expanded inhibition against a broad spectrum of mutations resistant to imatinib. Both nilotinib and dasatinib have demonstrated in vitro and in vivo clinical activity against different types of mutations and various forms of resistance. However, patients with T315I mutation do not obtain an advantage from these drugs and a third generation inhibitor ponatinib, a pan-BCR drug, was tested with significant results. In this review, we report the results of second- and third-generation TKIs tested as second or third line therapy in patients resistant and/or intolerant to previous inhibitors. [ABSTRACT FROM AUTHOR]

Background: A large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries. Patients and Methods: To describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75 years were retrospectively analyzed using data collected from 31 institutions in Italy. Results: The median age at imatinib start was 78.6 years [interquartile range (IR) 76.3-81.4], median time from diagnosis to imatinib start was 1.2 months (IR 0.5-3.7). The starting dose of imatinib was 400 mg/day in 144 patients (68.2 %), >400 mg/day in 4 patients (2.0 %), and <400 mg/day in 63 patients (29.8 %); overall, 94 patients (44.5 %) needed a dose reduction and 27 (12.7 %) discontinued imatinib for toxicity. Grade 3-4 hematologic and extrahematologic toxicities were observed in 40 (18.9 %) and 45 (21.3 %) patients, respectively. After a median observation of 29.8 months (IR 13.0-55.6), 203/211 patients had at least 6 months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2 %) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4 %) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5 %). Among the 129 patients with CCyR, 95 (46.7 %) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase ( p = 0.001) and grade 3-4 extrahematologic toxicity ( p = 0.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase ( p = 0.026), grade 3-4 extrahematologic toxicity ( p = 0.007), and lower initial dose of imatinib ( p = 0.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6 % (95 % CI 88.7-96.5) and 78.0 % (95 % CI 71.2-84.8), respectively. Conclusions: Results from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies. [ABSTRACT FROM AUTHOR]

Abstract: Tyrosine kinase inhibitors (TKIs) represent the gold standard therapy of chronic myeloid leukemia and, after being used in imatinib resistant patients, dasatinib and nilotinib are now also used in frontline. In this article, we review data about occurrence of side effects in several trials testing imatinib or second-generation tyrosine kinase inhibitors first line. Literature data about high-dose imatinib used front-line as single treatment or with different combinations is also examined. A literature search for relevant studies was undertaken mainly in PubMed. This review is aimed to summarize the safety of different treatments and to discuss the current management of most common side effects. Literature evidence supports the fact that side effects associated to TKIs seem to differ between agents, but most of side effects reported occur early within the treatment course. Second generation frontline TKIs reduce the incidence of most of side effects reported with imatinib and peculiar events observed are typically manageable through drug dose reduction or treatment interruption. [Copyright &y& Elsevier]

Abstract: Obesity, measured as body mass index (BMI), has been identified as a possible risk factor for several solid tumors as well as for chronic myeloid leukemia (CML). To date, no correlations have been reported in this latter disease between BMI at baseline and response to targeted therapies. We refer here on the impact of BMI on clinical response in 339 chronic phase (CP) CML patients treated with imatinib and 35 CP–CML patients treated frontline with nilotinib. If compared to patients with low BMI (<18.5–25), patients with increased BMI (>25–40) at diagnosis who received imatinib showed a significantly longer median time to achieve complete cytogenetic response (6.8months vs 3.3months, p =0.001), a reduced rate of major molecular response (77% vs 58%, p =0.01) which was also achieved in a longer median time (29months compared to 14months, p =0.01). Conversely, no differences were revealed with respect to BMI in patients treated frontline with nilotinib and also patients with increased BMI obtained rapidly CCyR and MMR with an incidence similar to that of underweight/normal weight patients. These results suggest that CML patients with increased weight at baseline should be followed and carefully monitored if treated with standard dose imatinib frontline for a possible early switch. [Copyright &y& Elsevier]

Dasatinib is a dual tyrosine kinase inhibitor active against ABL and Src family kinases, and is approved for the treatment of chronic myeloid leukemia (CML) patients in chronic, accelerated, or blast phase with resistance or intolerance to imatinib therapy, for newly diagnosed chronic phase patients, and for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia who have become resistant to or intolerant of other treatments. This review presents clinical data regarding different trials involving CML patients in different phases of the disease. Six-year follow-up of the Phase III dose-optimization study are described, showing overall survival of 71% with the current approved dose of 100 mg once daily. Three-year results of the randomized Phase III DASISION (DASatinib vs Imatinib Study In Treatment-Naïve CML patients) trial confirmed that dasatinib 100 mg once daily was superior to standard-dose imatinib in terms of achieving a faster and deeper molecular response, with similar activity regardless of baseline prognostic score. [ABSTRACT FROM AUTHOR]

Aim: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph- metaphases (MET-, when <20 cells were évaluable). Methods: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011. Results: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET- while 44 patients (24.2%) still presented Ph+ metaphases (MET+) «33%, 24 patients; >33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 x 109/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET- at 3 months. Among patients with CCyR/ MET- after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/METat 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET- at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001). Conclusions: The achievement of CCyR/MET- at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines. [ABSTRACT FROM AUTHOR]

Abstract: In 2006 European LeukemiaNet proposed recommendations to define several categories of chronic myeloid leukemia patients treated front-line with imatinib. In 2009 an update of these recommendations was published: whereas it is clear how important is to switch rapidly to a second line of treatment in failure patients, the correct treatment of patients with sub-optimal response is still a matter of debate. Several groups have indeed shown that prognosis of patients with sub-optimal cytogenetic response is similar to that of failure patients, whereas lack of data exists for patients with sub-optimal molecular response at 18months. In this article, we overview studies demonstrating prognostic implications of being suboptimal responders to imatinib as well as results of recent clinical trials testing new generation tyrosine kinase inhibitors in this setting. [Copyright &y& Elsevier]

Abstract: The impact of age as a poor prognostic factor in chronic myeloid leukemia (CML) has been well described. In the interferon era, elderly patients diagnosed as having chronic phase chronic myeloid leukemia (CP-CML) had shorter survival compared to younger patients. With the advent of target therapy with imatinib, several reports described improved responses in elderly late CP-CML patients treated with imatinib after IFN failure, with similar overall survival compared to younger population. Imatinib in newly diagnosed older patients showed similar rate of cytogenetic and molecular responses compared to younger patients. Few data are available relating elderly CML patients subset treated with second-generation TKIs after resistance/intolerance to imatinib: both nilotinib and dasatinib have demonstrated efficacy and limited toxicity profile as in younger patients. The aim of this review is, through the revision of published data, to highlight the fact that elderly CML patients can benefit from target therapy with limited adverse events. [Copyright &y& Elsevier]

Abstract: Imatinib has revolutionized treatment strategies for chronic myeloid leukemia patients: long-term overall survival was reported to be up to 80% at 8years of follow-up in respondent patients. Despite the straightforward results obtained, it has been estimated a failure rate per year of 2–4%. Several attempts to improve response have been made with high-dose of imatinib and with combination of standard dose with interferon, but both failed to ameliorate cytogenetic and molecular responses and long-term event-free and overall survival and no advantages were reported in high-risk patients. The introduction of second generation tyrosine kinase inhibitors in clinical practice allowed to rescue more than 50% of patients resistant or intolerant to imatinib. Both dasatinib and nilotinib were tested as single agent in first-line and then tested against imatinib standard dose: the results of phases II and III trials showed early and maintained complete cytogenetic response, rapid reduction of molecular burden and significant reduction of progression rate. At the present time, after FDA approval of both agents in first-line, several points of discussion are still unresolved. [Copyright &y& Elsevier]

Abstract: To highlight dasatinib role in the elderly, 125 unselected patients with CP-CML aged >60 years resistant/intolerant to imatinib were retrospectively evaluated. Grade 3–4 haematological and extra-haematological toxicities were reported in 39 (31.2%) and 34 (27.2%) patients; grade 3–4 haematological toxicity was higher in patients with 140mg starting dose (50.0% vs 19.6%, p =0.001). Grade 3–4 pleuro-pericardial effusions occurred in 10 patients (8.0%). Dose reductions were more common in patients with 140mg (88.4% vs 26.7%, p <0.001). Of 122 evaluable patients, 72 (59.1%) had cytogenetic response [12 (9.8%) partial, 60 (49.3%) complete]. Overall, 38/60 patients in complete CyR also achieved a molecular response. Cumulative OS at 24 and 48 months were 93.1% (95% CI 88.4–97.8) and 84.2% (95% CI 74.6–93.7). Dasatinib, at the recommended dose of 100mg/day, is effective and safe also in unselected elderly subjects. [Copyright &y& Elsevier]

Background: Imatinib has become first line therapy in chronic myeloid leukemia patients. Little is known about the infective consequences during the treatment with this drug in large series of chronic phase patients. Material and methods: From January 2001 to September 2006 we treated with imatinib 250 patients in first line (early CP) or after interferon failure (late CP), out of clinical trials and recorded all the bacterial and viral infections occurred. Results: We recorded a similar incidence of bacterial and viral infections both in first line and late CP patients (respectively, 16% and 13%) during 3.5 years of follow-up. Analysis of presenting features predisposing to infections revealed differences only in late CP patients, with elevated percentage of high Sokal risk patients and a more longer median time from diagnosis to start of imatinib. Conclusions: Opportunistic infections and reactivation of Herpes Zoster are observed during imatinib therapy at very low incidence. [ABSTRACT FROM AUTHOR]

Abstract: Tyrosine kinase inhibitors (TKI) have dramatically changed the management and the outcome of chronic myeloid leukemia (CML) patients. Imatinib is recognized as gold standard first-line therapy and impressive clinical and cytogenetic responses are obtained in the majority of chronic phase patients treated with this drug. Quantitative polymerase chain reaction (RQ-PCR) tool is used to monitor molecular residual disease, but practical issues are associated to measurement of molecular responses. Several evidences have now proved that molecular responses have prognostic significance: patients who achieve early molecular response are more likely to obtain durable cytogenetic response and to present less rate of disease progression. While some reports indicated that achieving major molecular response (MMR) represents the most important endpoint associated to best outcome, some other reports indicated that achievement of MMR does not improve the greatest clinical benefit brought by complete cytogenetic response. In this review, we discuss on the role of molecular monitoring, the significance of early response and its correlation with outcome, the significance of major and complete molecular response, the emphasized value of a stable molecular response, the early identification of resistance presenting with increased molecular level. [Copyright &y& Elsevier]

Abstract: Imatinib mesylate is currently the standard therapy for chronic myelogenous leukemia patients. Despite the remarkable results achieved with imatinib, the emergence of resistance to this drug has become a significant problem. Actually, two other second-generation tyrosine kinase inhibitors have been used for resistant/intolerant patients to imatinib. With the availability of oral tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia, questions relating to adherence to prescribed therapy have become an important issue. It has been demonstrated that the effectiveness of the treatment with imatinib requires high compliance to the prescribed dose of the drug for an indefinite period of time, whereas reduced adherence to therapy has been associated with delay in achieving cytogenetic or molecular response and/or possible development of resistance. The aim of this review is to discuss the importance of adherence, and the possible tools that we have to measure it, to improve our knowledge on possible underlying causes of non-adherence and the impact of non-adherence on hospitalization risk and healthcare cost through a systematic review of the data published to date. [ABSTRACT FROM AUTHOR]

Abstract: The age role was evaluated in 117 consecutive patients with newly diagnosed CML at our Institution treated with front-line Imatinib from 9/02 to 3/08. Forty patients (34.1%) aged ≥65 years and 77 (65.9%) <65 years. Thirty-four older patients (85%) had at least 1 comorbidity versus 39 younger patients (50.6%) (p <0.001). Complete cytogenetic response (CCyR) was achieved in 34/40 older patients (85%) as compared to 69/77 younger patients (89.6%), without statistically significant differences. Severe (grades 3–4 WHO) hematological and extra-hematological toxicities were more common in older patients (p =0.02 and p =0.017, respectively). Rates of permanent Imatinib discontinuation and dose reduction to 300mg or less were significantly higher in older patients (p =0.009 and p =0.001, respectively). In conclusion, Imatinib in older patients with newly diagnosed CML seems to have the same efficacy as in younger patients, but tends to be more toxic, leading to higher rates of discontinuation and dose reduction. To overcome this problem, future trials concerning best dosage in this subset of patients could be useful. [ABSTRACT FROM AUTHOR]

Abstract: Philadelphia-positive chronic myeloid leukemia (Ph+ CML) patients who are resistant to imatinib are commonly treated with second-generation tyrosine kinase inhibitors (TKIs). Limited data exist on the possible effects of these drugs on subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT).The outcome of 12 imatinib-resistant CML patients treated with dasatinib or nilotinib or both before allo-HSCT, was retrospectively analyzed. Patients were treated with second-generation TKIs for 1–17 months (median, 8). At the time of transplant, 3 patients were in complete cytogenetic response (CCgR), 3 patients in partial cytogenetic response (PCgR) and 6 patients were in less than PCgR. Donors were HLA-matched related in 4 cases and unrelated in 8 cases. Stem cell source was peripheral blood, bone marrow or cord blood in 6, 5 and 1 cases, respectively. All patients engrafted successfully and all but one achieved a full donor chimerism. Three patients experienced acute and chronic graft-versus-host disease. No cases of transplant-related mortality were recorded. Best response to allo-HSCT was complete molecular response (CMR) in 9 patients, major molecular response (MMR) in 1 patient and CCgR in 2 patients. Median follow-up was 16.5 months. At the last evaluation, 9 patients were in continuous CMR and 1 patient was in MMR; 2 patients had died of disease progression. Second-generation TKIs given before allo-HSCT do not negatively affect transplant engraftment and response rate, nor increases transplant-related toxicity. [Copyright &y& Elsevier]

Abstract: Imatinib mesylate is currently the standard of care for chronic myeloid leukemia (CML) patients in early chronic phase. However, the emergence of resistance and intolerance has dampened the enthusiasm for this drug. To overcome this phenomenon, different strategies have been developed, including novel targeted agents. Nilotinib, formerly known as AMN107, is a second-generation tyrosine kinase inhibitor 30-fold more potent than imatinib, with high affinity and selectivity on BCR/ABL, and also active against a wide range of mutant clones, except T315I mutation. Phase II trials of nilotinib showed high activity in imatinib-resistant or intolerant CML patients, whereas front-line treatment of the disease in chronic phase demonstrated rapid and stable cytogenetic responses and increasing molecular responses. We here review the development of nilotinib and the efficacy data in phase II and front-line trials. The aim of this review is to evaluate the pharmacology, pharmacokinetic and pharmacodynamic properties of the drug and the recent results of clinical trials performed in patients with CML and Ph+ acute lymphoblastic leukemia (ALL). [Copyright &y& Elsevier]

Abstract: The therapeutic efficacy of imatinib mesylate is based on its specific inhibition of several tyrosine kinases (TKs) implicated in the disease pathogenesis. These enzymes include BCR/ABL in patients with chronic myeloid leukaemia, PDGF-R alpha and beta in patients with certain myeloproliferative disorders and dermatofibrosarcoma protuberans and c-KIT in patients with gastrointestinal tumors. Most patients tolerate the drug well and apparently no metabolic abnormalities are evidenced during treatment. However, different metabolic effects have been reported as a consequence of imatinib inhibition during treatment of patients with CML. The aim of this review is to report the changes caused by imatinib on glucose, lypidic and bone metabolism. [Copyright &y& Elsevier]

Abstract: Chronic myeloid leukaemia (CML) patients in chronic phase (CP) are currently treated with a standard dose of imatinib of 400mg/daily. However, once in complete cytogenetic remission (CCR) it is possible that some patients maintain this status with reduced dose of the drug. Here, we describe five cases of CML in late CP, which were switched to imatinib while in CCR after interferon alpha (IFNα) and reached complete and stable molecular remission with intermittent drug administration at 400mg/every 20 days/month. [Copyright &y& Elsevier]

Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukemia (CML). The aim of our study was to analyse the frequency and type of hematological and non-hematological adverse events in our series of late and early chronic phase patients with CML treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological events were seen in 59 out of 150 (39%) late chronic phase (CP) patients: of these, 24% experienced toxicity Grade 3-4. Of the 100 early CP patients, 26 (26%) had hematological adverse event: 7% experienced toxicity Grade 3-4 (p = 0.0001). We found that only in early CP patients, the occurrence of hematological side effects of any grade within 6 months of therapy had a negative influence on cytogenetic response. We compared the incidence of non-hematological adverse events occurring in late and in early CP patients and found that in these latter, some side effects were more frequent, such as weight gain, periorbital edema, muscle cramps, skin rashes, diarrhea, weeping. On the contrary, we found that bone pain and hemorrhagic events were more common in late CP patients. Grade 3-4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of Grade 3-4, whereas in early CP patients, the most frequent events were nausea, weight gain and cutaneous rash. We have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response only in early CP patients. [ABSTRACT FROM AUTHOR]

Abstract: Imatinib mesylate is a selective inhibitor of the bcr/abl, c-kit and PDGF receptor tyrosine kinases. Its ocular toxicity is little known with mild periorbital oedema being the most commonly reported side effect. We here describe our experience on ocular complications in imatinib treated Ph+ CML patients, which consisted of a wide spectrum of adverse effects ranging from periobital oedema to serious adverse events such as glaucoma. [Copyright &y& Elsevier]

The article discusses the development of molecular treatments for chronic myeloid leukemia (CML), a clonal disease of hematopoietic stem cells characterized by the reciprocal translocation t(9;22)(q34;q11), which forms the Philadelphia (Ph) chromosome. Interferon-α (IFN-α) therapy produces hematological and cytogenetic responses leading to a 5-year survival rate of 57%. Imatinib mesylate specifically targets the breakpoint cluster region-Abelson kinase (BCR-ABL) hybrid protein in CML.

Abstract: To determine the impact on minimal residual disease by switching to imatinib chronic phase chronic myeloid leukaemia (CP-CML) patients responsive to interferon-alpha (IFNα), in stable complete cytogenetic response (CCR) but with persistent PCR positivity. Twenty-six Philadelphia positive (Ph+) CML patients in stable CCR after IFNα but persistently positive at PCR analysis during this treatment, were given imatinib mesylate at standard dose. At enrolment into the study, median IFN treatment and CCR duration were 88 months (range 15–202) and 73 months (range 10–148), respectively. Imatinib treatment resulted in a progressive and consistent decline of the residual disease as measured by quantitative PCR (RQ-PCR) in all but one of the 26 patients; at the end of follow-up, after a median of 32 months (range 21–49) of treatment, a major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%), and BCR/ABL transcripts were undetectable in 13 (50%). The achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response versus 18.97 for those who did not; p <0.001), but not with other clinical/biological disease characteristics. These results indicate that patients induced into CCR by IFN treatment represent a subset with very favourable prognosis, which can significantly improve molecular response with imatinib and further support investigative treatment schedules combining these two drugs. [Copyright &y& Elsevier]

Abstract: Since very few unusual BCR/ABL fusion transcripts in chronic myeloid leukemia have been reported, no clear evidence exists concerning their clinical and prognostic implications. We describe here a CML case with normal karyotype at standard cytogenetics and an atypical e6a2 BCR/ABL fusion transcript, presenting at diagnosis isolated thrombocytosis and mild leukopenia; the patient, who was tested negative for JAK2 mutation, obtained a complete response to imatinib. The few previous observations from literature are also reviewed. [Copyright &y& Elsevier]