Search

In 2016, the WHO included haemoglobin values within normal ranges as a diagnostic criterion for Polycythaemia Vera (PV). Since then, concerns have arisen that a large number of patients are undergoing unnecessary screening for PV. To address this issue, we estimated the prevalence of JAK2 p.V617F in individuals with elevated haemoglobin or haematocrit and developed and validated a screening algorithm for PV. A total of 15,366 blood counts performed in seven non-consecutive days were reviewed, of which 1001 were selected for subsequent JAK2 p.V617F mutation screening. Eight (0.8%) new JAK2 p.V617F-mutated cases were detected. From ROC curves, a two-step algorithm was developed based on the optimal cut-off for the detection of the JAK2 p.V617F mutation. The algorithm was prospectively validated in an independent cohort of 15,298 blood counts. A total of 1595 (10.4%) cases met the criterion for haemoglobin or haematocrit, of whom 581 passed to step 2 (3.8% of the total). The JAK2 p.V617F mutation was detected in 7 of the 501 patients tested, which accounts for 0.04% of the total cohort and 0.4% of patients with erythrocytosis. In conclusion, this data show that our two-step algorithm improves the selection of candidates for JAK2 p.V617F testing. [ABSTRACT FROM AUTHOR]

In this work we propose the use of image features based on visual perception for discriminating epithelium and stroma in histological images. In particular, we assess the capability of the following five visual features to correctly discriminate epithelium from stroma in digitised tissue micro-arrays of colorectal cancer: coarseness, contrast, directionality, line-likeliness and roughness. The use of features directly related to human perception makes it possible to evaluate the tissue׳s appearance on the basis of a set of meaningful parameters; moreover, the number of features used to discriminate epithelium from stroma is very small. In the experiments we used histologically-verified, well-defined images of epithelium and stroma to train three classifiers based on Support Vector Machines (SVM), Nearest Neighbour rule (1-NN) and Naïve Bayes rule (NB). We optimised SVM׳s parameters on a validation set, and estimated the accuracy of the three classifiers on a independent test set. The experiments demonstrate that the proposed features can correctly discriminate epithelium from stroma with state-of-the-art accuracy. [ABSTRACT FROM AUTHOR]

Low serum erythropoietin ( EPO) is a minor criterion of Polycythaemia Vera ( PV) but its diagnostic usefulness relies on studies performed before the discovery of JAK2 V617F mutation. The objective of the present study was to evaluate the diagnostic accuracy of serum EPO and JAK2 V617F allele burden as markers of PV as well as the combination of different diagnostic criteria in 287 patients (99 with PV, 137 with Essential Thrombocythaemia and 51 with non-clonal erythrocytosis). Low EPO showed good diagnostic accuracy as a marker for PV, with the area under the curve ( AUC) of the chemiluminescent-enhanced enzyme immunoassay ( CEIA) being better than that of radioimmunoassay ( RIA) (0·87 and 0·76 for CEIA and RIA, respectively). JAK2 V617F quantification displayed an excellent diagnostic accuracy, with an AUC of 0·95. A haematocrit >52% (males) or >48% (females) plus the presence of the JAK2 V617F mutation had a sensitivity and specificity of 79% and 97%, respectively. Adding low EPO or the JAK2 V617F allele burden did not improve the diagnostic accuracy for PV whereas the inclusion of both improved the sensitivity up to 83% and maintaining 96% specificity. Haematocrit and qualitative JAK2 V617F mutation allow a reliable diagnosis of PV. Incorporation of EPO and/or JAK2 V617F mutant load does not improve the diagnostic accuracy. [ABSTRACT FROM AUTHOR]

JAK2V617F-negative essential thrombocythemia (ET) is a heterogeneous disease including clonal cases and others without evidence of clonality. However, it is unknown if the detection of myeloid clonality in JAK2V617F-negative ET patients confers a different clinical outcome than those in whom clonal hematopoiesis cannot be demonstrated. The objective of the present study was to evaluate the clinical significance of clonality assessment in patients with JAK2V617F-negative ET. Clonality investigation including mutational status of MPL, TET2, and ASXL1 genes and human androgen receptor ( HUMARA) assay was performed in 73 JAK2V617F-negative cases out of 186 subjects consecutively diagnosed with ET in a single institution, at diagnosis or during follow-up. Mutations in MPL, TET2, and ASXL1 were observed in 7, 4, and 2 cases, respectively, whereas clonality by HUMARA assay was demonstrated in 21 out of 46 (46 %) female patients. With a median follow-up of 8 years, death, thrombosis, bleeding, and disease transformation were registered in 7, 10, 8, and 6 patients, respectively. No differences in thrombosis, bleeding or survival were observed according to clonality assessment. The probability of disease transformation at 10 years was higher in patients showing clonal hematopoiesis by presenting mutations in either MPL, TET2, or ASXL1 (64 versus 2 % in patients without mutations, p < 0.001) and in those with HUMARA clonality (35 versus 0 % in patients with polyclonal hematopoiesis, p < 0.004). In conclusion, disease transformation is associated with evidence of clonality in JAK2V617F-negative ET. [ABSTRACT FROM AUTHOR]

The modulation of JAK2 V617F allele burden dynamics was prospectively analysed in 47 patients (26 polycythaemia vera [PV] and 21 essential thrombocythaemia [ET]) treated with first-line hydroxyurea (HU) and compared with the JAK2 V617F dynamics of a control group of 45 PV and ET patients. A partial molecular response (PMR), according to European Leukaemia Net criteria, was observed in 27/47 (57%) patients. Median time to PMR was 14 months (3-66) with a probability of PMR at 3 years of 57%. A significant decrease in JAK2 V617F allele load was observed at 36 months both in PV and ET patients, being the reduction in PV higher than in ET patients ( P = 0·01). A haematocrit ≥0·45 L/L was associated with a higher probability of attaining a PMR (HR:3·4; 95%CI:1·02-11·6, P = 0·04). Control group showed a slight increase of JAK2 V617F allele burden over time. The reduction in the mutated allele load comparing treated patients versus controls was highly significant both in PV and ET, demonstrating a clear effect of HU on the JAK2 V617F allele burden. In conclusion, first-line HU can attain PMR in more than 50% of newly diagnosed PV and ET patients, with a continuous decrease of the JAK2 V617F allele burden in PV patients during treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The coexistence of cancer with other chronic conditions has substantial implications for treatment decisions and outcomes for both neoplasms and chronic disease. Reports have demonstrated the impact of comorbidities on survival in different hematologic disorders. Myelofibrosis (MF) guidelines do not consider the complex interrelations between MF and comorbidity. Several works have shown how MF patients have a wide variety and high burden of comorbidities and demonstrated that the comorbidity burden was significantly associated with an unfavorable impact on survival. These previous studies about comorbidity on MF are retrospective and consider the cumulative rather than individual comorbidity burden. The influence of individual comorbidities on outcome in MF patients has not been studied. We sought to identify the comorbidities in MF patients at diagnosis and to assess the influence of those different comorbidities on survival. Considering them individually may contribute to the personalization of MF management and optimizing outcomes. The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF. [ABSTRACT FROM AUTHOR]

This article discusses a rare case of a myeloid/lymphoid neoplasm with FGFR1 rearrangement, specifically the ETV6::FGFR1 fusion gene. The patient initially presented with T-lymphoblastic lymphoma and was treated with chemotherapy, but later relapsed with a mixed phenotype of T-lymphoblastic lymphoma and acute myeloid leukemia. The patient was refractory to various salvage chemotherapy regimens but showed a response to treatment with pemigatinib, a specific FGFR1-2-3 inhibitor. The patient underwent allogeneic hematopoietic stem cell transplantation and maintained a complete response. This case highlights the importance of genetic screening and targeted therapies in the management of myeloid/lymphoid neoplasms with FGFR1 rearrangement. [Extracted from the article]

Simple Summary: Myelofibrosis is a heterogeneous disease regarding its mutation landscape as well as its clinical presentation and outcome. A genomic classification with prognostic implications of myeloproliferative neoplasms has been previously proposed, however, this classification has hardly been implemented in myelofibrosis. The aim of our work is to evaluate this genomic classification in a large series of myelofibrosis patients from a single institution, taking into account whether cases are primary or secondary. We found that both primary and secondary myelofibrosis have distinctive molecular landscapes and that genomic profiling provides accurate information regarding prognosis and disease progression. Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that TP53 disruption/aneuploidy (n = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, p = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes (n = 72, 41%) represented the most frequent genomic group in PMF. Homozygous JAK2 mutation (n = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous JAK2 mutation (n = 22, 13%) was similarly distributed among PMF and SMF. MF with CALR mutation (n = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. TP53 disruption, chromatin/spliceosome mutation, and homozygous JAK2 mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 pandemic has favored the expansion of telemedicine. Philadelphia-negative chronic myeloproliferative neoplasms (Ph-MPN) might be good candidates for virtual follow-up. In this study, we aimed to analyze the follow-up of patients with Ph-MPN in Spain during COVID-19, its effectiveness, and acceptance among patients. We present a multicenter retrospective study from 30 centers. Five hundred forty-one patients were included with a median age of 67 years (yr). With a median follow-up of 19 months, 4410 appointments were recorded. The median of visits per patient was 7 and median periodicity was 2.7 months; significantly more visits and a higher frequency of them were registered in myelofibrosis (MF) patients. 60.1% of visits were in-person, 39.5% were by telephone, and 0.3% were videocall visits, with a predominance of telephone visits for essential thrombocythemia (ET) and polycythemia vera (PV) patients over MF, as well as for younger patients (< 50 yr). The proportion of phone visits significantly decreased after the first semester of the pandemic. Pharmacological modifications were performed only in 25.7% of the visits, and, considering overall management, ET patients needed fewer global treatment changes. Telephone contact effectiveness reached 90% and only 5.4% required a complementary in-person appointment. Although 56.2% of the cohort preferred in-person visits, 90.5% of our patients claimed to be satisfied with follow-up during the pandemic, with an 83% of positive comments. In view of our results, telemedicine has proven effective and efficient, and might continue to play a complementary role in Ph-MPN patients' follow-up. [ABSTRACT FROM AUTHOR]

In the midst of the COVID-19 pandemic, different vaccines in front of SARS-CoV-2 have been approved and administered in different vulnerable populations. As patients with cancer were excluded from pivotal trials of vaccination, little is known on their immunogenic response to these vaccines, particularly in patients with severely impaired immune system. In response to that uncertainty, the Spanish Society of Hematology and Hemotherapy launched an initiative aimed to provide recommendations for vaccination of the main hematological conditions. This document is based on the available information on COVID-19 outcomes, prior knowledge on vaccination in hematological patients, recent published data on serological response in oncohematological patients and expert opinions. New information about SARS-CoV-2 vaccination will be gathered in the near future, providing new scientific grounds to delineate the most adequate management of vaccination in patients with hematological diseases. The current limited data on SARS-CoV-2 vaccines in hematological patients represents a major limitation of this expert consensus opinion. In fact, the speed in which this field evolves may reduce their validity in the near future. [ABSTRACT FROM AUTHOR]

Mutations in the TET2 and ASXL1 genes have been described in approximately 14% and 8% of patients, respectively, with classic myeloproliferative neoplasms (MPN), but their role as possible new diagnostic molecular markers is still inconclusive. In addition, other genes such as IDH1, IDH2, and c-CBL have also been reported in several myeloid neoplasms. We have studied the mutational status of TET2 (complete coding region), ASXL1 (exon12), IDH1 (R132), IDH2 (R140 and R172), and c-CBL (exons 8 and 9) in 62 MPN patients (52 essential thrombocythemia (ET), five polycythemia vera (PV), and five primary myelofibrosis (PMF)) negative for both JAK2 (V617F and exon 12) and MPL (exon 10) mutations. Pathogenic alterations in the TET2 gene were detected in three out 52 ET cases (4.8%). ASXL1 gene pathogenic mutations were also detected in three cases (two ET and one PMF). One ET patient harbored, simultaneously, one TET2 and one ASXL1 mutations. Mutations in the TET2 and ASXL1 genes showed no association with the JAK2 46/1 haplotype. Analysis of a JAK2V617F-positive cohort of 50 ET patients showed no mutations in either the TET2 or ASXL1 genes. Regarding IDH1, IDH2, and c-CBL genes, no mutations were found in any patient. In conclusion, TET2 and ASXL1 pathogenic mutations are found in 8% of MPN lacking JAK2 and MPL mutations, whereas IDH1, IDH2, and c-CBL mutations are not detected in this subset of patients. [ABSTRACT FROM AUTHOR]

Abstract: Doxorubicin-containing chemotherapy is the standard regimen for elderly patients with aggressive lymphoma. However, many of them cannot receive it due to severe associated comorbidities. Toxicity and efficacy of intermediate doses of nonpegylated liposomal doxorubicin (NPLD) in modified-CHOP regimen±Rituximab were prospectively analyzed in 35 frail elderly patients (median age: 76 years) with previously untreated aggressive lymphoma with one or more severe comorbidities. NPLD at intermediate doses (30mg/m2) is effective and well tolerated in these patients. In addition, NT-proBNP levels >900ng/ml at diagnosis have demonstrated to be a good predictor for OS and PFS in this cohort of patients. [Copyright &y& Elsevier]

The article focuses on the analysis of mutations in messenger RNA splicing machinery genes such as SF3B1, SRSF2 and U2AF1 which have been identified in lymphoid and myeloid haematopoietic malignancies. Topics discussed include determination of SF3B1 gene modifications in thrombocythaemia and primary myelofibrosis, analysis of mutations in patients with polycythaemia vera disease, and use of polymerase chain reaction amplification and Sanger sequencing in the analysis of mutations.

Objectives: In patients with essential thrombocythemia (ET), after the JAK2V617F driver mutation, mutations in CALR are common (classified as type 1, 52‐bp deletion or type 2, 5‐bp insertion). CALR mutations have generally been associated with a lower risk of thrombosis. This study aimed to confirm the impact of CALR mutation type on thrombotic risk. Methods: We retrospectively investigated 983 ET patients diagnosed in Spanish and Polish hospitals. Results: With 7.5 years of median follow‐up from diagnosis, 155 patients (15.8%) had one or more thrombotic event. The 5‐year thrombosis‐free survival (TFS) rate was 83.8%, 91.6% and 93.9% for the JAK2V617F, CALR‐type 1 and CALR‐type 2 groups, respectively (P =.002). Comparing CALR‐type 1 and CALR‐type 2 groups, TFS for venous thrombosis was lower in CALR‐type 1 (P =.046), with no difference in TFS for arterial thrombosis observed. The cumulative incidence of thrombosis was significantly different comparing JAK2V617F vs CALR‐type 2 groups but not JAK2V617F vs CALR‐type 1 groups. Moreover, CALR‐type 2 mutation was a statistically significant protective factor for thrombosis with respect to JAK2V617F in multivariate logistic regression (OR: 0.45, P =.04) adjusted by age. Conclusions: Our results suggest that CALR mutation type has prognostic value for the stratification of thrombotic risk in ET patients. [ABSTRACT FROM AUTHOR]

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1-6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6-57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4-49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation. [ABSTRACT FROM AUTHOR]

Purpose: This study was aimed to analyze the association of very early molecular response to nilotinib with the achievement of deep molecular response (MR4) at 18 months. We hypothesized that the BCR-ABL1 levels during the first 3 months of therapy, and the kinetics of their descent in this period, could be predictive of deep molecular response thereafter. Methods: This substudy of the ENEST1st trial included 60 patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib, and BCR-ABL1IS levels were measured using GUS as the control gene. The analysis included seven time points during the first trimester of treatment (baseline and fortnightly thereafter). Results: The rates of MMR at 12 months, and of MR4 at 18 months (primary variable of the study), were 70 and 41%, respectively, similar to those obtained in the core study. BCR-ABL1IS ≤10% was achieved at 1, 1.5, 2 and 3 months in 50, 70, 83 and 93% of the patients, respectively. The observed shape of the BCR-ABL1IS descent was biphasic, with a faster slope during the first trimester and a median halving time (HT) of 11 days, the shortest reported in the literature. An HT ≤13 days was predictive of MMR at 12 months and MR4 at 18 months. Conclusions: The association of a shorter HT with response provides a rationale for exploring very early kinetics patterns in all patients treated with potent TKIs such as nilotinib. [ABSTRACT FROM AUTHOR]

Objectives Population-based studies have reported an increased incidence of skin cancer in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We have examined the risk factors for non-melanoma skin cancer (NMSC) in patients diagnosed with ET or PV during 1973-2012. Methods A case-control study was performed to compare the clinical and treatment-related data of 51 ET/PV patients who had NMSC with that of 401 patients who did not. We also evaluated whether polymorphisms in 12 genes involved in DNA integrity predisposed to NMSC. Results By multivariate logistic regression analysis, risk factors for NMSC were older age (OR: 1.7, 95% CI: 1.3-2.1, P < 0.001), male sex (OR: 2.1, 95% CI: 1.1-3.8, P = 0.023), higher cumulated hydroxycarbamide dose (OR: 1.3, 95% CI: 1.1-1.7, P = 0.017), and busulphan exposure (OR: 3.2, 95% CI: 1.05-10.0, P = 0.041). On the time-to-event prognostic model, factors independently associated with increased cumulative incidence of NMSC were age (5% increased risk per year; P < 0.001), male sex (91% increased risk; P = 0.022), and hydroxycarbamide exposure (22% increased risk; P = 0.065). No susceptibility gene variant was identified. Conclusions These findings suggest that the risk to develop NMSC in ET/PV patients results from the combined effect of common risk factors (age, male sex) together with cytoreductive treatment. [ABSTRACT FROM AUTHOR]

The article discusses a study on acute lymphoblastic leukaemia (ALL) in older patients. It informs that the older patients had poorer outcomes as a result of a poorer cytogenetic risk attributed to the presence of Philadelphia chromosome, Ph. The result of the study revealed that olderpatients with Ph+ ALL do not have poorer prognosis than those without Philadelphia chromosome, in the tyrosine kinase inhibitor (TKI) era.

Abstract: The association between seven polymorphisms in the genes hOCT1 and MDR1, encoding for imatinib transporter proteins, and the response to imatinib 400mg/daily was investigated in 65 patients newly diagnosed with chronic-phase chronic myeloid leukemia. The AA genotype at the rs6935207 hOCT1 polymorphic locus was not detected in patients with inadequate response to imatinib. The CC genotype at the rs1045642 (C3435T) MDR1 locus was associated with primary failure, whereas a T allele at the rs2032582 (G2677T/A) MDR1 locus seemed to protect from primary failure. Beside, the MDR1 haplotype 1236T-2677G-3435C was more frequently found in patients primarily resistant to imatinib. [Copyright &y& Elsevier]

To explore the gene expression signature in essential thrombocythemia (ET) patients in relation to JAK2V617F mutational status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients, not receiving cytoreductive treatment. A heterogeneous molecular signature characterized by two main gene expression patterns was found: one with an upregulation of inflammatory genes related to neutrophil activation and thrombosis, and the other with significantly lower expression of these genes. Supervised clustering analysis showed 30 genes differentially expressed between JAK2V617F-negative and JAK2V617F-positive ET patients. Among the JAK2V617F-negative, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and TRIB1) showed an abnormal expression pattern. In this group of patients, CISH, SOCS2, SOCS3 and PIM1 genes, all involved in JAK-STAT signalling pathway, presented a lower expression. A two-gene predictor model was built comprising FOSB and CISH genes, which were the best discriminators of JAK2V617F status. In conclusion, JAK2V617F-negative ET patients present a characteristic gene expression profile, different from JAK2V617F-positive patients. Other pathways, besides JAK-STAT, might be implicated in the pathophysiology of JAK2V617F-negative ET patients. Leukemia (2008) 22, 1368–1376; doi:10.1038/leu.2008.112; published online 15 May 2008 [ABSTRACT FROM AUTHOR]

Correction to: J Cancer Res Clin Oncol (2017) 143:2059-2066 DOI 10.1007/s00432-017-2445-z [ABSTRACT FROM AUTHOR]