Identifying patient subgroups with different trends of patient-reported outcomes (PROMs) after elective knee arthroplasty.

BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly being used to assess the effectiveness of elective total knee arthroplasty (TKA). However, little is known about how PROMs scores change over time in these patients. The aim of this study was to identify the trajectories of quality of life and joint functioning, and their associated demographic and clinical features in patients undergoing elective TKA. METHODS: A prospective, cohort study was conducted, in which PROMs questionnaires (Euro Quality 5 Dimensions 3L, EQ-5D-3L, and Knee injury and Osteoarthritis Outcome Score Patient Satisfaction, KOOS-PS) were administered to patients at a single center undergoing elective TKA before surgery, and at 6 and 12 months after surgery. Latent class growth mixture models were used to analyze the patterns of change in PROMs scores over time. Multinomial logistic regression was used to investigate the association between patient characteristics and PROMs trajectories. RESULTS: A total of 564 patients were included in the study. The analysis highlighted differential patterns of improvement after TKA. Three distinct PROMs trajectories were identified for each PROMs questionnaire, with one trajectory indicating the most favorable outcome. Female gender appears to be associated with a presentation to surgery with worse perceived quality of life and joint function than males, but also more rapid improvement after surgery. Having an ASA score greater than 3 is instead associated with a worse functional recovery after TKA. CONCLUSION: The results suggest three main PROMs trajectories in patients undergoing elective TKA. Most patients reported improved quality of life and joint functioning at 6 months, which then stabilized. However, other subgroups showed more varied trajectories. Further research is needed to confirm these findings and to explore the potential clinical implications of these results.

Correlation Between Co Levels in Hair and Blood of Patients Who Underwent Metal-on-metal Hip Arthroplasty.

Background: The purpose of this paper is to study the dependence of Co levels in hair on Co levels in blood after metal-on-metal (MoM) hip replacement and prove the suitability of hair analysis coupled to blood analysis in the decision process regarding implant revision evaluation. Methods: Hair samples of 19 MoM patients having both well-functioning and malfunctioning implants and Co mass concentration levels in blood between 0.2 µg L-1 and 221.0 µg L-1 were included. A method based on inductively coupled plasma mass spectrometry was validated and used to measure the Co level in hair. Results: The Co mass fraction in the hair of patients ranged between 0.011 mg kg-1 and 0.712 mg kg-1. A correlation analysis showed a statistically significant positive correlation (r = 0.932, P < .001) between Co in the hair and that in the blood in the full-level range and a statistically nonsignificant positive correlation (r = 0.595, P = .091) in the low-level range. Conclusions: A correlation between the Co level in the hair and that in the blood exists when the latter is clearly above the 7 µg L-1 mass concentration threshold suggested for implant revision evaluation. The correlation disappears when the Co level in blood approaches or falls down the mass concentration threshold and that in the hair approaches or falls within the normal population range of 0.004-0.14 mg kg-1. Accordingly, clinicians could consider a hair analysis coupled to a blood analysis to assess the revision of malfunctioning MoM implants that release metals in patient's body.

Patient reported outcomes measures (PROMs) trajectories after elective hip arthroplasty: a latent class and growth mixture analysis.

BACKGROUND: Patient-reported outcome measures (PROMs) are an extensively used tool to assess and improve the quality of healthcare services. PROMs can be related to individual demographic and clinical characteristics in patients undergoing hip arthroplasty (HA). The aim of this study is to identify distinct subgroups of patients with unique trajectories of PROMS scores and to determine patients' features associated with these subgroups. METHODS: We conducted a prospective, cohort study in which PROMs questionnaires (Euro Quality 5 Dimensions 3L, EQ-5D-3L, Euro-Quality-Visual-Analytic-Score, EQ-VAS, Hip disability and Osteoarthritis Outcome Score, HOOS-PS) were administered to patients undergoing elective HA pre-operatively, and at 6 and 12 months after surgery. For each measure, latent class growth analysis and growth mixture models were used to identify subgroups of patients with distinct trajectories of scores. Demografic and clinical predictors of the latent classes in growth mixture model were identified using a 3-step approach. RESULTS: We found three distinct trajectories for each PROM score. These trajectories indicated a response heterogeneity to the HA among the patients (n = 991). Patient's gender, ASA score, and obesity were significantly associated with different PROMs trajectories. CONCLUSIONS: We identified three distinct trajectories for each of the three PROMs indicators. Several demographic and clinical characteristics are associated with the different trajectories of PROMs at 6 and 12 months after HA and could be used to identify groups of patients with different outcomes following HA surgery. These findings underline the importance of patient-centered care, supporting the usefulness of integrating PROMs data alongside routinely collected healthcare records for guiding clinical care and maximizing patients' positive outcomes. TRIAL REGISTRATION: Protocol version (1.0) and trial registration data are available on the platform www. CLINICALTRIAL: gov with the identifier NCT03790267, posted on December 31, 2018.

Abductor muscle strengthening in THA patients operated with minimally-invasive anterolateral approach for developmental hip dysplasia.

OBJECTIVE: In developmental hip dysplasia (DDH) patients, the chronic dislocation of the femoral head with respect to the true acetabulum determines muscle contracture and atrophy, particularly of the abductor muscles, and leads to secondary osteoarthritis (OA) with severe motor dysfunction, pain and disability. The correct positioning when a total hip replacement (THR) is performed is fundamental to the recovery of gait function. Also, inadequate rehabilitation of the abductor muscles for pelvic stabilisation can be responsible for residual dysfunction. Consensus on a programme for abductor muscle strengthening in these patients is not currently available. The aim of this study was to evaluate the effectiveness of a specific program of exercises for strengthening the abductor muscles in these patients. METHODS: A multicentre, prospective, randomised clinical trial was carried out in an outpatient rehabilitation setting on 103 patients given THR for DDH through a minimally-invasive anterolateral approach. Patients were randomly divided into a Study Group, including 46 patients, and a Control Group, including 57 patients. All patients underwent standard early postoperative rehabilitation. In addition, the Study Group were given an extra 2-week rehabilitation once full weight-bearing on the operated limb was allowed, aimed at strengthening the abductor muscles. All patients were evaluated preoperatively, and at about 3 and 6 months postoperatively. Clinical measures (lower limb-length differences, hip range of motion, abductor muscle strength), and functional measures (WOMAC, HHS, 10mt WT, SF-12) were taken. RESULTS: Hip range of motion and functional outcome measures showed a progressive improvement at follow ups in both groups, significantly higher in the Study Group. In particular, abductor strength at 6 months post-op improved by 92.5% with respect to 35.7% in the Control Group. CONCLUSION: In addition to standard rehabilitation, a rehabilitation programme for strengthening the gluteal muscles in DDH patients who underwent THR determined an increase in muscle strength that improved functional performance and patient satisfaction.

Squeaking and other noises in patients with ceramic-on-ceramic total hip arthroplasty.

INTRODUCTION: Noise in ceramic-on-ceramic (CoC) total hip arthroplasty (THA) is a potential symptom of abnormal bearing wear. Squeaking and other prosthetic hip noises are multi-factorial phenomena that can be analysed and may provide prognostic information. METHODS: 46 patients with noisy CoC bearings were investigated using X-ray, computed tomography and joint fluid analysis, and classified into either high or low risk of ceramic liner fracture groups according to previously published guidelines. Noise events from the bearings of 16 high risk cases which were subsequently revised were compared with 30 patients in the low risk control group who did not undergo revision. Noise events were analysed for their physical characteristics using a standardised protocol and classified as either low frequency and short duration 'clicking' or long duration and high frequency 'squeaking'. RESULTS: The peak frequency of squeaking during forward walking was significantly higher for patients in the case group who were revised, compared with the control group. The patient-reported onset of squeaking (46 months postoperatively) was earlier than short-noise emissions (82 months). In the standardised sequence of movements, short-noise always occurred more frequently than squeaking. Small heads (28 mm) were more likely to develop short-noise, while large heads (⩾32 mm) were more likely to develop squeaking. DISCUSSION: Noise evaluation may provide additional value for predicting failure of CoC bearings, though some questions should be better investigated in a dedicated prospective trial.

Patient-reported outcome measures (PROMs) after elective hip, knee and shoulder arthroplasty: protocol for a prospective cohort study.

BACKGROUND: The number of hip, knee and shoulder arthroplasties continues to rise worldwide. The Organization for Economic Cooperation and Development has launched an initiative (called PaRIS Initiative) for the systematic collection of Patient Reported Outcome Measures (PROMs) in patients undergoing elective hip and knee arthroplasty. The Rizzoli Orthopedic Institute (IOR) was selected as a pilot center for the launch of the Initiative in Italy given that IOR hosts the Registry of Orthopedic Prosthetic Implants (RIPO), a region-wide registry which collects joint implant data from all the hospitals in the Emilia-Romagna Region. In this specific geographic area information related to PROMs after joint replacement is unknown. This paper describes the protocol of a study (PaRIS-IOR) that aims to implement the collection of a set of PROMs within an existing implant registry in Italy. The study will also investigate the temporal trend of PROMs in relation to the type of prosthesis and the type of surgical intervention. METHODS: The PaRIS-IOR study is a prospective, single site, cohort study that consists of the administration of PROMs questionnaires to patients on the list for elective arthroplasty. The questionnaires will be administered to the study population within 30 days before surgery, and then at 6 and 12 months following surgery. The study population will consist of consecutive adult patients undergoing either hip, knee or shoulder arthroplasty. The collected data will be linked with those routinely collected by the RIPO in order to assess the temporal trend of PROMs in relation to the type of prosthesis and the type of surgical intervention. DISCUSSION: The PaRIS-IOR study could have important implications in targeting the factors influencing functional outcomes and quality of life reported by patients after hip, knee and shoulder arthroplasty, and will also represent the first systematic collection of PROMs related to arthroplasty in Italy. TRIAL REGISTRATION: Protocol version (1.0) and trial registration data are available on the platform www.clinicaltrial.gov with the identifier NCT03790267 , first posted on December 31, 2018.

Ischemia-Modified Albumin Expression: Is there a Difference between Male and Female Subjects?

BACKGROUND: Ischemia-modified albumin (IMA) derives from naive albumin, modified in the binding region of bivalent ions, as cobalt and iron. The cobalt, released from some types of hip prosthesis seems to be metabolized differently in males and females but the iron ion is more prevalent than cobalt and is detectable in the healthy population. Our aim was to verify if there are any gender- and age-related differences in IMA concentrations and if IMA correlates with cobalt and iron-related proteins. METHODS: IMA, albumin, iron, ferritin, transferrin, and cobalt were measured in 50 men and 50 women divided into two age/fertility-homogeneous groups. RESULTS: Men < 45-years-old showed a statistically significant lower IMA concentration than men ≥ 45 and fertile and menopausal women. Considering all the population studied, IMA does not seem to be correlated with age and is distributed differently by gender; also, Co distribution was different between males and females. CONCLUSIONS: IMA did not correlate with cobalt, iron, ferritin, and transferrin in any group, except for fertile women where IMA presented a statistically significant correlation with serum iron values. Minor expression of IMA in young males together with the results obtained on serum iron in fertile females, could explain the higher accumulation of circulating Co in women compared to men and their different cobalt metabolism.

Metal-on-metal hip prostheses: correlation between debris in the synovial fluid and levels of cobalt and chromium ions in the bloodstream.

PURPOSE: Hip prostheses with metal-on-metal (MoM) coupling can release cobalt-chromium particles and ions. The aim of this work is to verify the correlation between particles in the synovial fluid and circulating ions. METHODS: Forty patients were enrolled; particles from synovial fluid were analysed by SEM­EDX (Scanning Electron Microscopy-Energy Dispersion X-rays analysis) and levels of circulating Co and Cr were assayed by ICP-MS (inductively-coupled plasma mass spectrometry). RESULTS: In 16 cases we did not find any particles in the synovial fluid and the Co level in whole blood was 0.05­4.42 ppb; in seven with few particles the blood level was 2.2­15.6 ppb; in six cases with several particles the level was 5.0­54.3 ppb; finally, in 11 cases we isolated not only Co-Cr particles, but also Cr particles with low or absent Co and in these patients the circulating level of Co was 23.8­109.6 ppb. Co in serumand Cr level both whole blood and serum have shown a similar trend to Co; the correlation between all these values and the corresponding particles is statistically significant in all cases. CONCLUSION: Co and Cr both in serum and whole blood represents a systemic representation of the particle release at local level and can therefore be used to confirm a diagnosis and monitor the wear process of MoM articular prostheses.

Molecular monitoring of BCR-ABL transcripts after allogeneic stem cell transplantation for chronic myeloid leukemia.

The monitoring of minimal residual disease (MRD) through low sensitivity real-time (RT) polymerase chain reaction (PCR) analysis of BCR-ABL transcripts allows early detection of chronic myeloid leukemia (CML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT). The introduction of more sensitive techniques, such as RT quantitative (Q)-PCR, may lead to an overestimation of the risk of CML relapse. In this study, we reviewed the results of peripheral blood RT Q-PCR in CML patients who underwent allogeneic HSCT from 1983 to 2007. In our laboratory, RT Q-PCR analysis was routinely performed since 2002. Eighty-seven of 189 patients had available RT Q-PCR data; 63 patients had at least 3 RT Q-PCR analyses assessable. Fifty-two of 63 patients (83%) had, at least once, detectable transcript levels, but with an BCR-ABL/ABL ratio <.1% defined as .1% confirmed by the finding of Ph+ cells in bone marrow. No patients with persistent undetectable transcripts relapsed (P = .19). Relapse did not correlate with the number of occurrences of

Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party.

The median age of chronic myeloid leukemia (CML) patients is ~60 years, and age is still considered an important prognostic factor, included in Sokal and EURO risk scores. However, few data are available about the long-term outcome of older patients treated with imatinib (IM) frontline. We analyzed the relationship between age and outcome in 559 early chronic-phase CML patients enrolled in 3 prospective clinical trials of Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working Party, treated frontline with IM, with a median follow-up of 60 months. There were 115 older patients (≥ 65 years; 21%). The complete cytogenetic and major molecular response rates were similar in the 2 age groups. In older patients, event-free survival (55% vs 67%), failure-free survival (78% vs 92%), progression-free survival (62% vs 78%), and overall survival (75% vs 89%) were significantly inferior (all P < .01) because of a higher proportion of deaths that occurred in complete hematologic response, therefore unrelated to CML progression (15% vs 3%, P < .0001). The outcome was similar once those deaths were censored. These data show that response to IM was not affected by age and that the mortality rate linked to CML is similar in both age groups. This trial was registered at www.clinicaltrials.gov as #NCT00514488 and #NCT00510926.

Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis.

Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a "warning" for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a "warning" category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.

Philadelphia-positive acute lymphoblastic leukemia patients already harbor BCR-ABL kinase domain mutations at low levels at the time of diagnosis.

BACKGROUND: In patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point mutations in the BCR-ABL kinase domain. We aimed to assess: (i) in how many patients BCR-ABL kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy. DESIGN AND METHODS: We retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphia-positive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample. RESULTS: Mutations at relatively low levels (2-4 clones out of 200) could be detected in all patients--eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib. CONCLUSIONS: Our results suggest that the BCR-ABL kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors.

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.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The response to imatinib and interferon-alpha is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive chronic myeloid leukemia patients in early chronic phase.

Before the introduction of imatinib, interferon alpha-based regimens were the gold standard for treatment of early chronic phase chronic myeloid leukemia patients. The combination of IFN-alpha with imatinib is currently being investigated in at least two large clinical trials, the German CML Study IV and the French SPIRIT trial. We reviewed the cytogenetic and molecular responses of 76 early chronic phase chronic myeloid leukemia patients who were treated with imatinib and interferon-alpha and of 419 early chronic phase chronic myeloid leukemia patients treated with imatinib alone front-line. The complete cytogenetic response rate was higher in the IM+IFN-alpha group than in the imatinib group at six months (60% vs. 42%; P=0.003), but not at 48 months (88% vs. 88%). The durability of the complete cytogenetic response was similar in the two groups with 94% and 91% of complete cytogenetic responders in continuous complete cytogenetic response at 48 months (P=0.56). The major molecular response rate was higher in the IM+IFN-alpha group at six months (58% vs. 34%; P=0.0001) and 12 months (67% vs. 47%; P=0.001) but not later on (65% vs. 57% at 48 months; P=0.25). Overall and progression free survival were comparable in the two groups; a significant trend to a better event free survival was observed in patients treated with PegIFNalpha (91% vs. 78%; P=0.02). These data suggest that the response to the combination treatment is more rapid. It is not yet known how much a rapid reduction will influence the longer-term overall and progression free survival, and the cure rate.

Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP.

In chronic myeloid leukemia, different methods are available to monitor the response to therapy: chromosome banding analysis (CBA), interphase fluorescence in situ hybridization (I-FISH), and real-time quantitative polymerase chain reaction (RT-Q-PCR). The GIMEMA CML WP (Gruppo Italiano Malattie Ematologiche Adulto Chronic Myeloid Leukemia Working Party) has performed a prospective study to compare CBA and I-FISH for the definition of complete cytogenetic response (CCgR). Samples (n = 664) were evaluated simultaneously by CBA and I-FISH. Of 537 cases in CCgR, the number of positive nuclei by I-FISH was less than 1% in 444 cases (82.7%). Of 451 cases with less than 1% positive nuclei by I-FISH, 444 (98.4%) were classified as CCgR by CBA. The major molecular response rate was significantly greater in cases with I-FISH less than 1% than in those with I-FISH 1% to 5% (66.8% vs 51.6%, P < .001) and in cases with CCgR and I-FISH less than 1% than in cases with CCgR and I-FISH 1% to 5% (66.1% vs 49.4%, P = .004). I-FISH is more sensitive than CBA and can be used to monitor CCgR. With appropriate probes, the cutoff value of I-FISH may be established at 1%. These trials are registered at http://www.clinicaltrials.gov as NCT00514488 and NCT00510926.

Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia.

Nilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph(+) CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at ClinicalTrials.gov as NCT00481052.

Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34- cell population with intrinsic resistance to imatinib.

We show the molecular and functional characterization of a novel population of lineage-negative CD34-negative (Lin(-)CD34(-)) hematopoietic stem cells from chronic myelogenous leukemia (CML) patients at diagnosis. Molecular karyotyping and quantitative analysis of BCR-ABL transcript demonstrated that approximately one-third of CD34(-) cells are leukemic. CML Lin(-)CD34(-) cells showed kinetic quiescence and limited clonogenic capacity. However, stroma-dependent cultures induced CD34 expression on some cells and cell cycling, and increased clonogenic activity and expression of BCR-ABL transcript. Lin(-)CD34(-) cells showed hematopoietic cell engraftment rate in 2 immunodeficient mouse strains similar to Lin-CD34(+) cells, whereas endothelial cell engraftment was significantly higher. Gene expression profiling revealed the down-regulation of cell-cycle arrest genes and genes involved in antigen presentation and processing, while the expression of genes related to tumor progression, such as angiogenic factors, was strongly up-regulated compared with normal counterparts. Phenotypic analysis confirmed the significant down-regulation of HLA class I and II molecules in CML Lin(-)CD34(-) cells. Imatinib mesylate did not reduce fusion transcript levels, BCR-ABL kinase activity, and clonogenic efficiency of CML Lin(-)CD34(-) cells in vitro. Moreover, leukemic CD34(-) cells survived exposure to BCR-ABL inhibitors in vivo. Thus, we identified a novel CD34(-) leukemic stem cell subset in CML with peculiar molecular and functional characteristics.

Pancreatic enzyme elevation in chronic myeloid leukemia patients treated with nilotinib after imatinib failure.

An increase in the serum concentration of pancreatic enzymes (amylase and lipase) was reported in a proportion of imatinib-resistant and/or intolerant Philadelphia-positive chronic myeloid leukemia patients treated with nilotinib. Acute pancreatitis was very rare, and the relevance of these laboratory alterations remains unknown. We report on 8 chronic myeloid leukemia patients who developed serum lipase/amylase elevation during treatment with nilotinib. After a median follow-up of 26 months, none of these patients developed an acute pancreatitis or clinical signs of pancreatic disease. Pancreatic hyperenzymemia never led to permanent drug discontinuation and required nilotinib temporary interruption in one case only. The median cumulative duration of dose interruptions and response to treatment were comparable in patients with or without pancreatic enzyme elevation. The mechanisms of action of nilotinib on pancreatic enzymes deserves to be investigated: however, in our experience, the relevance of pancreatic hyperenzymemia was clinically very limited.

Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors.

Dasatinib and nilotinib are tyrosine kinase inhibitors (TKIs) developed to overcome imatinib resistance in Philadelphia-positive leukemias. To assess how Bcr-Abl kinase domain mutation status evolves during sequential therapy with these TKIs and which mutations may further develop and impair their efficacy, we monitored the mutation status of 95 imatinib-resistant patients before and during treatment with dasatinib and/or nilotinib as second or third TKI. We found that 83% of cases of relapse after an initial response are associated with emergence of newly acquired mutations. However, the spectra of mutants conferring resistance to dasatinib or nilotinib are small and nonoverlapping, except for T315I. Patients already harboring mutations had higher likelihood of relapse associated with development of further mutations compared with patients who did not harbor mutations (23 of 51 vs 8 of 44, respectively, for patients who relapsed on second TKI; 13 of 20 vs 1 of 6, respectively, for patients who relapsed on third TKI).

Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party.

Imatinib mesylate has become the treatment of choice for chronic myeloid leukemia (CML): the standard dose for chronic- phase (CP) CML is 400 mg daily. Response rates are different according to Sokal score, being significantly lower in intermediate and high Sokal risk patients. Phase 1 and 2 trials have shown a dose-response effect and high-dose imatinib trials in early CP CML showed better results compared with standard dose. Our study is the first prospective trial planned to evaluate the efficacy and tolerability of high-dose imatinib in previously untreated intermediate Sokal risk CML patients. Seventy-eight patients were treated with 400 mg imatinib twice daily: complete cytogenetic response (CCgR) rates at 12 and 24 months were 88% and 91%; moreover, at 12 and 24 months 56% and 73% of CCgR patients achieved a major molecular response. The incidence of adverse events was slightly higher than reported by the most important standard-dose trials. With a median follow-up of 24 months, 3 patients progressed to advanced phase. In intermediate Sokal risk newly diagnosed CML patients, high-dose imatinib induced rapid and high response rates, apparently faster than those documented in the International Randomized Study of IFN and Imatinib for the same risk category. These clinical trials are registered at www.clinicaltrials.gov as no. NCT00510926.