Risk scores predicting disease progression in early-stage CLL: Comparative analysis and usefulness of IGHV subset #2 to improve their accuracy.

BACKGROUND: Overall, the prognosis of patients with chronic lymphocytic leukemia (CLL) in the early phase of the disease (Rai 0, Binet A) is favorable; some patients never require therapy. However, some patients require intervention shortly after diagnosis. In the past decade, several risk scores (RS) have been developed to predict disease progression, yet some patients are misclassified. On the other hand, IGHV subset 2 (IGHV2) predicts poor outcomes. METHODS: A retrospective and multicentric study was conducted to compare the accuracy of five different RS (IPS-E, CR0, AIPS-E, CLL-IPI, and Barcelona-Brno) to predict disease progression in 781 stage A previously untreated patients with CLL. As an exploratory analysis, it was further investigated whether the inclusion of the IGHV2 as a poor prognostic parameter improved the accuracy of RS. RESULTS: All the scores identified a similar group of patients with CLL in early stage with low-, intermediate-, and high-risk progression. Discrimination was high and similar in all RS (c-index = 0.74-0.79, area under the curve = 0.7-0.75), as well as calibration (p = .98) and parsimony, although CLL-IPI showed the best results (Akaike information criterion = 441). A total of 34.4% of patients were categorized within the same RS and concordance was at least moderate between RS. CONCLUSION: Moreover, the results suggest that IGHV2 may improve the accuracy of RS.

Validation of the Artificial Intelligence Prognostic Scoring System for Myelodysplastic Syndromes in chronic myelomonocytic leukaemia: A novel approach for improved risk stratification.

Chronic myelomonocytic leukaemia (CMML) is a rare haematological disorder characterized by monocytosis and dysplastic changes in myeloid cell lineages. Accurate risk stratification is essential for guiding treatment decisions and assessing prognosis. This study aimed to validate the Artificial Intelligence Prognostic Scoring System for Myelodysplastic Syndromes (AIPSS-MDS) in CMML and to assess its performance compared with traditional scores using data from a Spanish registry (n = 1343) and a Taiwanese hospital (n = 75). In the Spanish cohort, the AIPSS-MDS accurately predicted overall survival (OS) and leukaemia-free survival (LFS), outperforming the Revised-IPSS score. Similarly, in the Taiwanese cohort, the AIPSS-MDS demonstrated accurate predictions for OS and LFS, showing superiority over the IPSS score and performing better than the CPSS and molecular CPSS scores in differentiating patient outcomes. The consistent performance of the AIPSS-MDS across both cohorts highlights its generalizability. Its adoption as a valuable tool for personalized treatment decision-making in CMML enables clinicians to identify high-risk patients who may benefit from different therapeutic interventions. Future studies should explore the integration of genetic information into the AIPSS-MDS to further refine risk stratification in CMML and improve patient outcomes.

Are silver-coated megaprostheses superior to uncoated megaprostheses in managing chronic end-stage periprosthetic hip and knee infection?

INTRODUCTION: Outcomes for silver coated megaprostheses (SC-MP) used in cases of end-stage periprosthetic joint infection (PJI) have not been clearly defined. Although attractive, concerns over implant longevity and the risk of infection relapse exist among the scientific community. Therefore, we sought to investigate the effect of silver coating in lower-extremity MPs used in such difficult-to-treat scenarios. The study's primary hypothesis was that the periprosthetic infection control rate would be higher in patients with silver-coated implants. MATERIALS AND METHODS: Non-interventional retrospective study with a historical comparison group. We identified all consecutive end-stage hip and knee PJI cases at our center managed with exchange arthroplasty using a silver-coated megaprosthesis from January 2016 to March 2021, these cases were compared with a historical cohort of end-stage PJI cases managed with uncoated megaprostheses. The main outcome studied was infection control rate. Secondarily, we analyzed the short-to-medium-term survivorship of this type of silver-coated implant. RESULTS: Fifty-nine megaprostheses used in cases of end-stage PJI were included in this study. We identified 30 cases of chronic hip or knee PJI in which a silver-coated modular megaprosthesis was implanted. Our non-coated megaprosthesis (NC-MP) historical group included 29 patients. Both groups had similar demographic characteristics. We found no statistically significant differences in infection control rate (80% vs. 82.8%, p = 0.47) or implant survivorship (90% vs. 89.65%, p = 1) after a mean follow-up for SC-MP of 46.43 months, and 48 months for the non-coated MP group. In relapsed cases, there were no differences in infection eradication after DAIR (66% SC-MP vs. 60% NC-MP success rate, p = 1). During the follow-up we observed one case of skin argyria without further repercussion. CONCLUSION: We were unable to confirm our initial hypothesis that use of silver-coated implants in end-stage PJI scenarios may be associated with better outcomes in terms of infection control or implant survivorship.

Cemented vs cementless stems for revision arthroplasties due to Vancouver B2 periprosthetic hip fracture.

PURPOSE: According to Vancouver classification, B2 type fractures are most often treated with removal of the loose stem and implantation of a long stem that bypasses the fracture site. However, there is a controversy about the stem fixation that should be used: cemented or cementless. Hence, this study aims to compare cemented and cementless stems in prosthetic revision due to Vancouver B2 (VB2) periprosthetic hip fracture. METHODS: A retrospective study was done including all the patients treated with stem exchange due to VB2 periprosthetic hip fracture in a tertiary hospital between 2015 and 2022. Patients were divided into two groups according to the stem fixation used: cemented or cementless. Functional outcomes, hospital stay, surgical time, complication rate, and mortality were compared between the two groups of patients. RESULTS: Of the 30 included patients, 13 (43.4%) were treated with cementless stems and 17 (56.7%) with cemented stems. There were no statistically significant differences in age, gender, anesthesia risk scale (ASA) or functional capacity prior to the intervention. Patients treated with cementless stems had a higher complication and reintervention rate than those treated with cemented stems: 62 and 45% versus 34 and 6% (p = 0.035; p = 0.010), respectively. Furthermore, in the group of cementless stems a higher proportion of non-union was found (53.8% vs. 17.6%; p = 0.037). Also, the hospital stay (33 vs. 24 days; p = 0.037) and the time to full weight-bearing (21 days vs. 9 days; p < 0.001) were longer in the cementless stem group. CONCLUSION: Cemented fixation in stem revision due to Vancouver B2 periprosthetic hip fracture could be an optimal option with faster recovery which could decrease the rate of complications and reintervention, without compromising the fracture healing and patient mortality. Thus, this option can be considered when an anatomical reduction can be obtained, especially in elderly patients with multiple comorbidities in which a less aggressive surgical option should be considered.

Temporary immobilization methods for closed low-energy ankle fracture-dislocations: comparative analysis of a retrospective cohort.

PURPOSE: Ankle fracture-dislocations (AFD) often necessitate staged management involving temporary external fixation (EF) due to mechanical instability or blistering. However, limited literature exists on the optimal temporary immobilization method for low-energy closed AFD. This study compared baseline patient and fracture characteristics, along with clinical and radiological outcomes between AFD initially immobilized with EF versus splinting. METHODS: A retrospective cohort study was conducted involving patients with AFD temporarily immobilized using EF or splinting, followed by definitive open reduction and internal fixation. Quality of reduction (QOR) was assessed for each patient post-initial immobilization and after the definitive surgery. RESULTS: The study encompassed 194 patients: 138 treated with a splint (71.1%) and 56 (28.9%) with EF. Secondary loss of reduction had occurred in three patients who were splinted (2.2%). The mean ages in the EF and splint groups were 63.2 and 56.1 years, respectively (p = 0.01). Posterior malleolus fracture (PMF) and blisters were more prevalent in EF patients (69.6% vs. 43.5% for PMF and 76.8% vs. 20.3% for blisters, respectively; p = 0.05 and p < 0.01). Postoperative complication rates were 8.9% for EF versus 10.9% for splinting (p = 0.69). Satisfactory final QOR was attained in 79.8% of patients treated with a splint versus 64.3% with EF (p = 0.02). CONCLUSION: Patients immobilized by EF presented with poorer baseline characteristics and had more unstable injuries. Nevertheless, postoperative complication rates were comparable. Thus, EF appears to be a valuable tool for standardizing outcomes in AFD patients with a less favorable prognosis.

Vancouver B2 periprosthetic hip fractures treatment: fix or replace? A retrospective study comparing both techniques.

INTRODUCTION: Vancouver B2 periprosthetic hip fractures involve stem stability and they have been classically treated with revision surgery. Crucial factors such as age, clinical comorbidities and functional status are often neglected. The current study aims to compare clinical outcomes between patients treated with open reduction and internal fixation (ORIF) or femoral stem exchange. METHODS: This is a retrospective study that includes all Vancouver B2 periprosthetic hip fractures in a tertiary referral hospital from 2016 to 2020. Patients were divided into two groups: Group 1. Patients treated with an ORIF and Group 2. Patients treated with stem replacement. The outcomes that were compared between groups included demographic data, functional capacity, complications and mortality. RESULTS: 29 periprosthetic Vancouver B2 fractures were finally analyzed. 11 (37.9%) were treated with ORIF (Group 1) and 18 (62.1%) by stem replacement (Group 2). Surgery time (143 vs. 160 min), hemoglobin drop (1.8 vs. 2.5 g/dL) and hospital stance (25.5 vs. 29.6 days) were shorter in Group 1. According to complications, 18.2% of patients in the ORIF group had orthopedic complications compared with 44.4% in the revision group. In the revision group, 3 cases needed a two-stage revision and one of these revisions ended up with a resection arthroplasty (Girdlestone). The first-year mortality rate was 27% in Group 1 and 11% in Group 2. DISCUSSION: ORIF treatment seems to be a less aggressive and complex procedure which can lead to a faster general recovery. Revision surgery can imply a higher risk of orthopedic complications which can be severe and may require further aggressive solutions. The ORIF group mortality was similar to the proximal femur fracture rate (20-30%). In conclusion, ORIF treatment seems to be a good option especially in fragile patients with low functional demand when anatomical reduction is possible.

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease.

In the European LeukemiaNet favourable risk category, allogeneic haematopoietic stem cell transplantation (alloSCT) is not indicated in first complete remission for patients with acute myeloid leukaemia (AML) with NPM1 mutations (ELNfav NPM1 AML), although a proportion of these patients will relapse. Given the prognostic importance of measurable residual disease (MRD), CETLAM-12 considered a pre-emptive intervention in patients with molecular failure (MF). We analyzed 110 ELNfav NPM1 AML patients achieving complete remission (CR) after induction chemotherapy. Two-year cumulative incidence of relapse (CIR), overall survival (OS) and leukaemia-free survival (LFS) were 17%, 81·5% and 82%, respectively. Forty-six patients required additional therapy for MF (n = 33) or haematological relapse (HemR; n = 13), resulting in a molecular LFS (molLFS) and a cumulative incidence of MF at two years of 61% and 38% respectively. Two-year OS for these 46 patients was 66%, with a different outcome between patients with MF (86%) and HemR (42%) (P = 0·002). Quantitative NPM1 detection at different timepoints was predictive of molLFS; an MRD ratio (NPM1mut/ABL1 × 100) cut-off of 0·05 after first consolidation identified two cohorts with a two-year molLFS of 77% and 40% for patients below and above 0·05, respectively. In conclusion, MRD-based pre-emptive intervention resulted in a favourable outcome for ELNfav NPM1 AML patients.

Molecular profiling refines minimal residual disease-based prognostic assessment in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia.

Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in high-risk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosome-negative B-cell progenitor ALL patients treated according to the Programa Español de Tratamientos en Hematología protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRD-negative after induction therapy.

The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients.

The prognostic significance of low-hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)-oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5-year cumulative incidence of relapse (CIR) of low-hypodiploid B-cell precursor (BCP)-ALL was significantly higher than that of high-hypodiploids (52% vs. 12%, P = 0.013). Low-hypodiploid BCP-ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5-year CIR (17% vs. 66%, P = 0.090) than low-hypodiploids aged >35 years. Older adults and elderly low-hypodiploid BCP-ALL patients show dismal prognosis although achieving an end-induction good MRD response.

A novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia.

A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for minimal residual disease assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-single nucleotide variants. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by sequencing, evaluating the level of mutations detected at diagnosis. The predictive value of minimal residual disease status by sequencing, multiparameter flow cytometry, or quantitative polymerase chain reaction analysis was determined by survival analysis. The sequencing method achieved a sensitivity of 10-4 for single nucleotide variants and 10-5 for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnostic data set). Sequencing-determined minimal residual disease positive status was associated with lower disease-free survival (hazard ratio 3.4, P=0.005) and lower overall survival (hazard ratio 4.2, P<0.001). Multivariate analysis showed that minimal residual disease positive status determined by sequencing was an independent factor associated with risk of death (hazard ratio 4.54, P=0.005) and the only independent factor conferring risk of relapse (hazard ratio 3.76, P=0.012). This sequencing-based method simplifies and standardizes minimal residual disease evaluation, with high applicability in acute myeloid leukemia. It is also an improvement upon flow cytometry- and quantitative polymerase chain reaction-based prediction of outcomes of patients with acute myeloid leukemia and could be incorporated in clinical settings and clinical trials.

Bone marrow WT1 levels in patients with myeloid neoplasms treated with 5-azacytidine: Identification of responding patients.

INTRODUCTION: Increased levels of Wilms' tumor (WT1) mRNA have been used to establish risk categories in patients with acute myeloid leukemia (AML). Raised values of WT1 have been associated with progression in myelodysplastic syndrome (MDS). METHODS: We retrospectively analyzed the available bone marrow (BM) samples from 115 patients with myeloid neoplasms obtained before and during treatment with 5-azacytidine. A threshold of 100 copies in BM was used to define risk groups: group 1: patients with WT1 levels always below < 100 copies; group 2: cases with initial WT1 levels greater than 100 copies but with a conversion to sustained levels below 100; and group 3: cases with follow-up WT1 levels greater than 100. RESULTS: Twenty patients were included in group 1, 17 in group 2, and 78 in group 3. Survival analysis showed statistically significant differences in terms of OS between groups (p: 0.016). Patients in group 2 showed the best 5-year overall survival (OS). In multivariate analysis, only the cytogenetic risk category and receiving an allogeneic hematopoietic stem cell transplantation (HCT) independently predicted the survival. CONCLUSIONS: Further studies are needed to assess whether BM WT1 levels could be useful to predict the survival of patients with myeloid neoplasms treated with 5-azacytidine.

Bone Marrow WT1 Levels in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplasia: Clinically Relevant Time Points and 100 Copies Threshold Value.

The outcome of allogeneic hematopoietic stem cell transplantation (HCT) in patients with myeloid malignancies is better in those without minimal residual disease (MRD) than in those with MRD+, as assessed by multiparametric flow cytometry (MPFC). WT1 quantitation also has been used to assess the probability of relapse in acute myelogenous leukemia (AML) treated with chemotherapy. We analyzed the clinical value of normalized bone marrow WT1 levels as a measure of the expanded myeloid progenitor compartment in a consecutive series of 193 adult patients with myeloid malignancies who underwent HCT. Bone marrow WT1 levels before the HCT, at the first bone marrow aspirate after infusion, and in the follow-up samples after HCT were determined by means of real-time PCR using the European LeukemiaNet normalized method. We sought to clarify the prognostic relevance in terms of overall survival (OS), progression-free survival (PFS), and cumulative incidence of relapse (CIR). Based on earlier experience in AML, we selected a threshold of 100 copies, defining 2 groups: patients with <100 WT1 copies and those with ≥100 copies. Patients with <100 WT1 copies before HCT (median time, 36 days; range, 4 to 268 days) had a better OS, PFS, and CIR than those with ≥100 copies (40 ± 1 versus 29 ± 6 days, P = .004; 35 ± 9 versus 26 ± 6 days, P = .002; and 29 ± 7 versus 37 ± 6 days, P = .051). In the first bone marrow study after the HCT (median time, 42 days; range 14 to 157 days, respectively), patients with <100 WT1 copies also had better outcomes in terms of OS, PFS, and CIR (40 ± 7 versus 31 ± 9 days, P = .025; 36 ± 7 versus 30 ± 8 days, P = .004; and 29 ± 6 days versus 54 ± 9, P < .001, respectively). At this time point, bone marrrow samples with >100 copies also included patients who were negative for MRD as assessed by MPFC (19 of 32). During the HCT follow-up, patients with sustained WT1 levels <100 copies showed a marked benefit in terms of OS, PFS, and CIR even compared with those with only a single measurement >100 copies (mean, 68 ± 11 versus 26 ± 7 days, P < .001; 63 ± 11 versus 20 ± 8 days, P < .001; and 20 ± 8 vs. 71 ± 8 days, P < .001, respectively). Standardized bone marrow WT1 levels using a 100-copy threshold in samples obtained before HCT, at leukocyte recovery, and during follow-up provided relevant prognostic information in patients with myeloid malignacies submitted to HCT.

Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies.

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.

Feasibility of the AML profiler (Skyline™ Array) for patient risk stratification in a multicentre trial: a preliminary comparison with the conventional approach.

Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline™ Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL-PTD, FLT3-ITD and TKD, NPM1 and CEBPAdm mutations. Purified RNA was used to assess RUNX1-RUNX1T1, PML-RARα and CBFß-MYH11 rearrangements. RNA remnants underwent gene expression profiling analysis using the AML profiler, which detects chromosomal aberrations: t(8;21), t(15;17), inv(16), mutations (CEBPAdm, ABD-NPM1) and BAALC and EVI1 expression. Thirty cases were successfully analysed with both methods. Five cases had FLT3-ITD. In one case, a t(8;21) was correctly detected by both methods. Four cases had inv(16); in one, the RNA quality was unsatisfactory and it was not hybridized, and in the other three, the AML profiler detected the genetic lesion - this being a rare type I translocation in one case. Two cases with acute promyelocytic leukaemia were diagnosed by both methods. Results for NPM1 mutations were concordant in all but two cases (2/11, non-ABD mutations). Analysis of costs and turnaround times showed that the AML profiler was no more expensive than the conventional molecular approach. These results suggest that the AML profiler could be useful in multicentre trials to rapidly identify patients with AML with a good prognosis. Copyright © 2016 John Wiley & Sons, Ltd.