Choice of Frontline Tyrosine-Kinase Inhibitor and Early Events in Very Elderly Patients With Chronic Myeloid Leukemia in Chronic Phase: A "Campus CML" Study.

OBJECTIVES: The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP-CML patients. METHODS: A retrospective analysis was conducted on 332 CP-CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the "Campus CML" project. RESULTS: Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second-generation TKIs (2G-TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G-TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra-hematologic toxicity (9.5%), with no significant difference between IM and 2G-TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G-TKIs. CONCLUSIONS: IM was in our Centers the preferred frontline therapy for older CP-CML patients, with increasing utilization after the introduction of generic formulations. However, 2G-TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population.

Recovering from chronic myeloid leukemia: the patients' perspective seen through the lens of narrative medicine.

PURPOSE: The main objective of this study is to gain a deeper understanding of how patients suffering from chronic myeloid leukemia (CML) cope with their illness. The study aims to reconstruct the subjective meaning-making process related to CML in order to gain insights into the impact the disease has on patients' emotions and everyday lives, as well as to explore the psychological impact of their being presented with the chance to suspend their therapy and recover from the disease. METHODS: Data were gathered from a qualitative study conducted in Italy on 158 Italian CML patients. Basing the study on the narrative inquiry approach, the patients were required to describe their patient journey in a qualitative narrative diary. These contained prompts to elicit the free expression of their needs, expectations, and priorities. A lexicographic analysis was carried out with T-LAB software and in particular a thematic analysis of elementary contexts (TAECs) and a word association analysis (WAA). RESULTS: The TAEC detected four thematic clusters related to two factors (temporal frame and contextual setting) that explained the variance among the narratives. The WAA evidenced a wide variety of emotions, both positive and negative, as patients reacted to the possibility of interrupting their therapy. CONCLUSIONS: A better understanding of patients' experiences can offer insights into promoting the development of more sustainable healthcare services and into therapeutic innovation aimed at improving patients' quality of life and at engaging them more in their treatment. The findings of this study can also help make medical professionals more aware of the patient's burden and help them identify potential interactions and emotional levers to improve clinical relationships.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Histological subtypes of Hodgkin's disease in the setting of HIV infection.

The relative incidence of Hodgkin's disease (HD) has been found to have increased approximately seven times in HIV-infected patients. We analyzed the histological distribution of HIV-associated HD with the aim of clarifying purported difference(s) from de novo HD. References on HIV/AIDS-associated HD were retrieved from the most complete databases. Nineteen articles were the subject of our analysis. Seventeen of them reported data on the histological type of HIV/AIDS-associated HD patients; the route of infection and age of the patients were also considered when available. According to the Peto's methodology, histological types were compared with those from two large studies in the United States on de novo HD: 3,245 cases from the Surveillance, Epidemiology, and End Results (SEER) and 1,140 from Stanford University. The analysis of the two groups showed statistically significant differences (p<0.001) in the percentage of all histological types and odds ratios (OR) of the pooled effect of 0.4 (95% CI: 0.3-0.6) for lymphocyte predominance (LP), 0.3 (95% CI: 0.2-0.4) for nodular sclerosis (NS), 3.2 (95% CI: 2.6-3.8) for mixed cellularity (MC), and 6.3 (95% CI: 4.5-8.8) for lymphocyte depletion (LD). Comparison with the Stanford University series yielded similar results. Whilst retrospective and based on a limited number of cases, our data confirm a higher incidence of unfavorable histological subtypes in HIV-infected patients and show a reduction in the observed cases of good prognosis subtypes. Prospective studies, with careful histological observations, are required to better evaluate the characteristics of the LP subtype in the special setting of HIV infection.

Heterogeneity of clonal development in chronic myeloproliferative disorders.

Recent reports have suggested a previously unexpected variability in the expression of the dominant neoplastic clone in myeloproliferative disorders (MPD). We evaluated 49 female patients with MPD and informative at the X-linked androgen receptor (AR) locus to establish the X chromosome inactivation pattern of hemopoietic cells. Whereas in chronic myelogenous leukemia (CML) the granulocytes (PMN) were uniformly of monoclonal origin, a striking heterogeneity of clonal development was found in PMN from patients with other MPD, with up to 50% of them expressing a polyclonal pattern of X inactivation.

Mutations of the HFE gene and the risk of hepatocellular carcinoma.

The discovery of the C282Y and H63D point mutations in the hereditary hemochromatosis-associated HFE gene allows us to study the molecular basis of congenital and acquired iron overload disorders. In hereditary hemochromatosis an increased frequency of the C282Y and, to a lesser extent, of the H63D mutations has been established, but their role in other conditions associated with iron overload and their prevalence in the normal population are still under investigation. We sought to determine the presence of such mutations, and their possible involvement in the multi-step neoplastic transformation of the hepatocytes, in patients diagnosed with hepatocellular carcinoma, a frequent complication of iron-induced liver cirrhosis occurring in untreated hereditary hemochromatosis subjects. The frequency of the C282Y and H63D mutations was determined in DNA from 12 patients with hepatocellular carcinoma and with no clinical signs of hereditary hemochromatosis. The frequency of the mutations was also determined in 130 normal subjects. A germline C282Y mutation was found in none of the hepatocellular carcinoma patients; the frequency of the H63D mutation was not increased, compared to the 130 controls. The allele frequencies of the C282Y and H63D mutations in the normal population were 0.042 and 0.185, respectively. In conclusion, we suggest that the hereditary hemochromatosis-related mutations of the HFE gene do not play a significant role in the pathogenesis of hepatocellular carcinoma.

X chromosome inactivation patterns in normal females.

Since one of the two X chromosomes is randomly inactivated at an early stage of female embryonic development, X-linked markers have been used to study the origin and development of various neoplastic disorders in affected heterozygous women; clonality assays have provided a useful tool to the understanding of the mechanisms underlying the development of neoplasia. Recently, a technique of clonal analysis has been devised that takes advantage of a highly polymorphic short tandem repeat within the X-linked human androgen receptor (AR) gene, resulting in a heterozygosity rate approaching 90%. The rapid expansion of the number of women now suitable for X inactivation analysis has however given rise to new controversies, one of the more troublesome being the possibility of a modification of the pattern of X- chromosome inactivation pattern in blood cells of elderly women. In the present study we analyze with the AR assay a group of 166 healthy females aged between 8 and 94 years, with no history of genetic or neoplastic familial disorders. We failed to find any correlation between age and X- chromosome inactivation pattern (r = 0.17), even subdividing the subjects in different age groups according to the criteria used by other researchers, and therefore reaffirm that, when tested for with well-standardized and accurate criteria, extremely unbalanced inactivation of the X chromosome is a truly uncommon phenomenon in normal women.

Familial Hodgkin's disease: a disease of young adulthood?

Familial Hodgkin's disease (FHD) is estimated to represent approximately 4.5% of all cases of Hodgkin's disease (HD). Shared environmental factors, such as Epstein-Barr virus and other viral agents, and genetic determinants have all been proposed to explain familial aggregation of HD. In order to compare the characteristic features of FHD with those of the much more common sporadic form, we reviewed 28 articles on FHD, published between 1972 and 1995, and analyzed in further detail data from 18 papers, reporting on a total of 328 patients. The male-to-female ratio of the FHD population examined was 1.5, similar to that reported for sporadic HD, and lower than the one suggested for FHD by some authors. On the other hand, a significant difference was found between sporadic and familial HD according to age at diagnosis; that is, only one major peak between 15 and 34 years was present in the group of patients with FHD. Further investigation of FHD in young adulthood may provide insight into the hypothesis of a genetic or infectious etiology of the disease.

Unusual bone marrow relapse of Hodgkin's disease with typical Pel-Ebstein fever.

We report the unusual case of a 43-year-old man with a diagnosis of clinical stage I A mixed cellularity Hodgkin's disease (HD), who relapsed 4 years after diagnosis with exclusive bone marrow involvement and a cyclic variation in body temperature typical of Pel-Ebstein fever. In the absence of clinical and laboratory signs of infection, a restaging of the lymphoma was performed. Total-body CT scan revealed no parenchymal or lymph node involvement, while a bone-marrow biopsy was positive for the presence of Reed-Sternberg cells. Therefore, the patient was started on combination chemotherapy, which promptly induced a normalization of the temperature curve. The presence of typical Pel-Ebstein fever, which is reported to be very rare, in association with bone marrow localization as the only site of relapse, suggests a relationship between these two rare manifestations of the disease.