Real-life use of ropeg-interferon α2b in polycythemia vera: patient selection and clinical outcomes.

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy.

Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: the "RAMP" Italian multicenter prospective study.

Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.

A prospective survey of febrile events in hematological malignancies.

The Hema e-Chart prospectively collected data on febrile events (FEs) in hematological malignancy patients (HMs). The aim of the study was to assess the number, causes and outcome of HM-related FEs. Data were collected in a computerized registry that systematically approached the study and the evolution of FEs developing in a cohort of adult HMs who were admitted to 19 hematology departments in Italy from March 2007 to December 2008. A total of 869 FEs in 3,197 patients with newly diagnosed HMs were recorded. Fever of unidentified origin (FUO) was observed in 386 cases (44.4%). The other causes of FE were identified as noninfectious in 48 cases (5.5%) and infectious in 435 cases (50.1%). Bacteria were the most common cause of infectious FEs (301 cases), followed by fungi (95 cases), and viruses (7 cases). Mixed agents were isolated in 32 episodes. The attributable mortality rate was 6.7% (58 FEs). No deaths were observed in viral infection or in the noninfectious groups, while 25 deaths were due to FUO, 16 to bacterial infections, 14 to fungal infections, and three to mixed infections. The Hema e-Chart provided a complete system for the epidemiological study of infectious complications in HMs.

Liposomal amphotericin B in the treatment of visceral leishmaniasis in immunocompromised patients.

Leishmaniasis is a zoonosis caused by a protozoan of the Leishmania genus. First-line treatment for all forms is currently represented by the use of antimony derivatives, although toxic effects and the number of resistant strains in both immunocompromised and immunocompetent patients is increasing. Liposomal amphotericin B (L-AMB) is less toxic, more effective, and better tolerated, especially in human immunodeficiency virus-negative immunocompromised patients. We present 2 cases of transplanted patients affected by visceral leishmaniasis treated successfully with L-AMB.

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.

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.

Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma.

PURPOSE: To assess the clinical relevance of minimal residual disease (MRD) in patients with multiple myeloma (MM), 50 patients were monitored while they were in complete clinical remission (CCR) after autologous or allogeneic stem-cell transplantation. PATIENTS AND METHODS: Stringent molecular monitoring using clonal markers based on rearranged immunoglobulin heavy-chain genes was performed in 44 of 50 MM patients in CCR. Molecular clinical remission (MCR) was defined as more than one consecutive negative polymerase chain reaction (PCR) test result. RESULTS: Twelve (27%) of 44 molecularly monitored patients achieved MCR; four of the 12 became PCR-positive, and one of these four relapsed. In comparison with patients who did not achieve MCR, patients who achieved MCR had a significantly lower relapse rate (41% v 16%; P <.05) and longer relapse-free survival (35 v 110 months; P <.005). Fourteen of 26 patients in CCR who had received allografts were evaluated on a molecular basis: seven (50%) of the 14 achieved MCR and did not relapse; one of the seven remaining patients relapsed. Thirty of 47 patients in CCR who received autografts were evaluated on a molecular basis: five (16%) of the 30 achieved MCR; two of these five became PCR-negative, and one of these two relapsed. Ten of the 25 remaining patients later relapsed. For these nonrandomized groups, the higher MCR rate after allograft procedures was statistically significant (P <.01; Fisher's exact test). CONCLUSION: MCR can be obtained in a relatively high proportion of MM patients who have achieved CCR after undergoing allograft procedures and in a smaller fraction of patients after undergoing autograft procedures. In approximately one fourth of MM patients who achieve CCR after transplantation, it may be possible to keep the disease burden constantly below the PCR threshold. Because MCR was associated with prolonged relapse-free survival, these patients could have a relatively favorable clinical outcome.

Nuclear factor-erythroid 2 (NF-E2) expression in normal and malignant megakaryocytopoiesis.

Although the transcription factor nuclear factor-erythroid 2 (NF-E2) is known to be functionally linked to the megakaryocytic lineage, little is known about its role in malignant megakaryocytes. We used real-time RT-PCR and Western blotting to investigate expression of NF-E2 and its partner, MafG, in CD34-derived normal (five cases) and malignant megakaryocytes from essential thrombocythemia (ET) patients (eight cases) and in megakaryoblastic cell lines. We also quantitated the mRNA of the thromboxane synthase (TXS) gene, which is directly regulated by NF-E2. Although real-time RT-PCR showed that both a and f NF-E2 isoforms were significantly reduced with respect to the normal counterpart both in ET megakaryocytes and in cell lines (P < or = 0.01), western blotting revealed decreased NF-E2 protein expression only in the latter. However, both the NF-E2a/MafG mRNA ratio (P < or = 0.01) and TXS (P< or = 0.01) mRNA expression were significantly reduced in megakaryocytes from ET patients and cell lines with respect to healthy subjects. These two findings provide strong indirect evidence of altered activity of the a isoform of NF-E2 in malignant megakaryocytes, raising the possibility that NF-E2 could play a role in megakaryocyte transformation.

Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey.

A prospective cohort study was conducted in nine hematology wards at tertiary care centres or at university hospitals located throughout Italy from January 2009 to December 2012. All of the cases of bacterial bloodstream infection (BBSI) occurring in adult patients with hematologic malignancies were included. A total of 668 bacterial isolates were recovered in 575 BBSI episodes. Overall, the susceptibility rates of Gram-negative bacteria were 59.1% to ceftazidime, 20.1% to ciprofloxacin, 79.1% to meropenem, 85.2% to amikacin, 69.2% to gentamicin and 69.8% to piperacillin/tazobactam. Resistance to third-generation cephalosporins was found in 98/265 (36.9%) of Enterobacteriaceae isolates. Among Klebsiella pneumoniae strains, 15/43 (34.9%) were resistant to carbapenems. Of 66 Pseudomonas aeruginosa isolates, 46 (69.7%) were multidrug resistant. Overall, the susceptibility rates of Gram-positive bacteria were 97.4% to vancomycin and 94.2% to teicoplanin. Among the monomicrobial cases of BBSI, the 21-day mortality rate was significantly higher for those caused by Gram-negative bacteria compared to those caused by Gram-positive bacteria (47/278, 16.9% vs. 12/212, 5.6%; p < 0.001). Among Gram-negative bacteria, the mortality rate was significantly higher for BBSI caused by K. pneumoniae, P. aeruginosa, and Acinetobacter baumannii. Our results confirm the recently reported shift of prevalence from Gram-positive to Gram-negative bacteria as causative agents of BBSIs among patients with hematologic malignancies and highlight a worrisome increasing frequency in antimicrobial resistance among Gram-negative bacteria.

Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis.

We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (⩽ 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P = 0.04), longer survival (100% versus 96%, P = 0.05) and better combined-EFS (86% versus 71%, P = 0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients.

Lack of compensatory megakaryocytopoiesis in HIV-1-seropositive thrombocytopenic individuals compared with immune thrombocytopenic purpura patients.

In this study we demonstrate that HIV-1-seropositive thrombocytopenic individuals, in contrast with immune thrombocytopenic purpura (ITP) patients, fail to have a compensatory increase of megakaryocytopoiesis. The in vitro growth of bone-marrow megakaryocyte progenitors (CFU-MK) and the production of granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1 and IL-6 by bone-marrow mononuclear adherent cells and peripheral blood (PB) light-density mononuclear cells were studied in 12 HIV-1-seropositive thrombocytopenic individuals with respect to 12 ITP patients and 15 normal controls. In HIV-1-seropositive thrombocytopenic individuals, CFU-MK size (number of megakaryocytes per colony) was similar to normal controls but significantly lower (P less than 0.05) than in ITP patients. IL-1 and IL-6 production was similar in the three groups of subjects. On the other hand, GM-CSF production by bone-marrow mononuclear adherent cells in HIV-1-seropositive thrombocytopenic individuals was similar to normal controls but significantly (P less than 0.05) lower than in ITP patients, whereas GM-CSF production by PB light-density mononuclear cells was markedly (P less than 0.05) defective compared with both normal controls and ITP patients. The positive correlation between number and size of CFU-MK and production of GM-CSF by bone-marrow mononuclear adherent cells, observed in all three groups of subjects, demonstrates the central role of GM-CSF in the control of megakaryocytopoiesis.

Recombinant alpha-interferon 2b in the treatment of HIV-related thrombocytopenia.

OBJECTIVE: To assess the efficacy and the mechanism of action of alpha-interferon (alpha-IFN) in the treatment of HIV-related thrombocytopenia. METHODS: Thirteen HIV-positive subjects [nine men and four women with severe thrombocytopenia (platelets, < or = 30 x 10(9)/l)] were treated with alpha-IFN 2b alone at a dose of 3 x 10(6) U three times a week for 5 weeks. Haematological parameters, platelet kinetic and bone-marrow myeloid progenitor cultures [megakaryocyte colony-forming units (CFU-MK); granulocyte macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E)] were evaluated before and after treatment in responsive subjects. RESULTS: Seven out of 13 subjects showed a partial response (platelets, 50-149 x 10(9)/l) after alpha-IFN 2b therapy. Platelet survival as evaluated by 111In-oxine significantly increased, while platelet turnover showed a slight but not statistically significant increase after treatment. The growth of bone-marrow myeloid progenitor cells decreased after alpha-IFN 2b therapy, again without statistical significance. CONCLUSION: alpha-IFN 2b may increase the platelet count in HIV-positive subjects with severe symptomatic thrombocytopenia by prolonging platelet survival. The immunomodulatory and antiviral action of this drug may be responsible for prolonged platelet survival.

Sequential vidarabine infusion in the treatment of polyoma virus-associated acute haemorrhagic cystitis late after allogeneic bone marrow transplantation.

Late onset haemorrhagic cystitis (HC) occurs in 20-30% of allogeneic bone marrow transplant patients. Human polyomavirus BK (BKV) (or less frequently adenovirus) may be involved in the pathogenesis of viral HC and can represent a serious post-transplant complication. Diagnosis and treatment of viral HC can be difficult and has an uncertain outcome. We report the efficacy of sequential vidarabine in the treatment of a patient with severe BKV-associated HC, despite the delay in implementing therapy. Bone Marrow Transplantation (2000) 25, 319-320.

Hypercoagulability in patients undergoing autologous or allogeneic BMT for hematological malignancies.

Severe thrombotic alterations, such as veno-occlusive disease of the liver, may occur in the early phase following high-dose chemoradiotherapy and BMT. In this study, performed in patients with hematological malignancies subjected to allogeneic (10 cases) and autologous (20 cases) BMT, we have monitored laboratory hemostatic parameters to better understand the pathogenetic mechanism of thrombosis and particularly of veno-occlusive disease. Prothrombin time, activated partial thromboplastin time, plasma fibrinogen, markers of hypercoagulability (thrombin-antithrombin complex and prothrombin fragment F1+2); natural anticoagulants (protein C, protein S and antithrombin) together with fibrinolytic parameters (plasminogen, alpha 2-antiplasmin, tissue-plasminogen activator, plasminogen activator inhibitor and D-dimer) were assessed before transplant, on day 0 and weekly for 1 month thereafter. A hypercoagulability state, not related to an impairment of the anticoagulant and fibrinolytic systems, was documented before and after autologous and allogeneic transplant. Two patients developed veno-occlusive disease: they did not show any difference from the other patients before transplant while they presented a decrease of the natural anticoagulants along with altered fibrinolytic parameters only at the clinical onset of veno-occlusive disease. In conclusion, in this study a state of marked hypercoagulability was documented in BMT patients and the hemostatic laboratory parameters evaluated were not able to predict the occurrence of the thrombotic complications.

Endothelium and bone marrow transplantation.

Thrombotic complications may occur early after marrow transplantation and many data suggest that endothelial injury plays a pivotal role in their pathogenesis. Since plasma thrombomodulin and P-selectin are thought to be of value as markers of vascular endothelial cell membrane injury, we investigated their plasma concentration in bone marrow transplant patients aiming better to clarify the degree of endothelial involvement. Plasma thrombomodulin and P-selectin were monitored in 25 patients without thrombotic complications before transplant, on day 0 and weekly for 1 month thereafter, while in three patients who developed VOD monitoring continued until day +52. These proteins were in the normal range in all the uncomplicated patients and in two with reversible VOD, while they were always very high in the only patient who developed very severe and lethal VOD. In conclusion, we suggest that endothelial activation/damage occurs rarely in the course of BMT for hematological malignancies; we were able to document endothelial injury in only one patient with very severe thrombotic complication.

Characterization of autotransplant-related thrombocytopenia by evaluation of glycocalicin and reticulated platelets.

Thrombocytopoiesis of 21 multiple myeloma patients undergoing single or double transplant regimen was characterized by measuring the level of reticulated platelets and plasma glycocalicin. Since reticulated platelets are an index of thrombopoietic activity and glycocalicin plasma values are related to platelet damage and turnover, it may be possible to perform a novel type of analysis of the thrombopoietic compartment during the mobilizing regimen and during transplant-related chemotherapy. Patients underwent mobilizing therapy and first transplant. Some randomized patients also underwent a second transplant with mobilized peripheral blood stem cells. The results show that the percentage of reticulated platelets decreased after therapy and then gradually increased in the recovery phase either during first or second transplant. By contrast, the percentage of reticulated platelets increased until day +8 and then gradually decreased during the mobilizing regimen. The glycocalicin index (glycocalicin plasma value normalized for the individual platelet count) increased significantly both during the course of mobilization and after transplant-related chemotherapy when the platelet number was at its nadir. However, the glycocalicin index was more elevated after transplant-related chemotherapy than after the mobilizing regimen. Our findings suggest that chemotherapy-related thrombocytopenia may be due to a dual mechanism: thrombocytopenia results from decreased platelet production in addition to increased platelet damage and possible destruction.

Granulocytic sarcomas: clinical, diagnostic and therapeutical aspects.

Granulocytic sarcomas (GS) are extramedullary tumor masses of immature myeloid cells most frequently associated with acute myeloblastic leukemia. We report our diagnostic, clinic and therapeutic approaches in the treatment of 6 patients affected by GS who presented with different localizations and symptoms: mediastinal mass with chest pain, rectal tumor with bowel occlusion, bladder mass with acute kidney failure, quadriceps tumor with pain, vertebral localization with pain and bowel mass with pain, respectively. The correct diagnosis of GS by bone biopsy, the immunohistological evaluation of the tumor masses, the prompt use of active drugs in the first line therapy schedule as for acute myeloblastic leukemia are the parameters for the achievement of the long-term remission.

Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology).

The aims of the study were to analyze the clinical and epidemiological characteristics and treatments for patients who developed zygomycosis enrolled in Italy during the European Confederation of Medical Mycology of medical mycology survey. This prospective multicenter study was performed between 2004 and 2007 at 49 italian Departments. 60 cases of zygomycosis were enrolled: the median age was 59.5 years (range 1-87), with a prevalence of males (70%). The majority of cases were immunocompromised patients (42 cases, 70%), mainly hematological malignancies (37). Among non-immunocompromised (18 cases, 30%), the main category was represented by patients with penetrating trauma (7/18, 39%). The most common sites of infection were sinus (35%) with/without CNS involvement, lung alone (25%), skin (20%), but in 11 cases (18%) dissemination was observed. According to EORTC criteria, the diagnosis of zygomycosis was proven in 46 patients (77%) and in most of them it was made in vivo (40/46 patients, 87%); in the remaining 14 cases (23%) the diagnosis was probable. 51 patients received antifungal therapy and in 30 of them surgical debridement was also performed. The most commonly used antifungal drug was liposomal amphotericin B (L-AmB), administered in 44 patients: 36 of these patients (82%) responded to therapy. Altogether an attributable mortality rate of 32% (19/60) was registered, which was reduced to 18% in patients treated with L-AmB (8/44). Zygomycosis is a rare and aggressive filamentous fungal infection, still associated with a high mortality rate. This study indicates an inversion of this trend, with a better prognosis and significantly lower mortality than that reported in the literature. It is possible that new extensive, aggressive diagnostic and therapeutic procedures, such as the use of L-AmB and surgery, have improved the prognosis of these patients.

Relief of intractable pruritus in polycythemia vera with recombinant interferon alfa.

Following reports that recombinant interferon alfa (rIFN alpha), besides inducing clinical and hematologic remission in polycythemia vera (PV), can also resolve intractable pruritus, we used rIFN alpha to treat 13 PV patients complaining of severe pruritus refractory to conventional treatment (venesection and/or cytostatics). rIFN alpha was administered intramuscularly three times a week at a dosage of 3.0 x 10(6) U. Eight patients (61.5%) reported a > or = 50% reduction of pruritus, which occurred within 2-8 weeks from the start of rIFN alpha treatment, leading to a substantial improvement in their quality of life. Three patients had to stop rIFN alpha within the first month of therapy because of unacceptable side effects. Thus rIFN alpha seems to be capable of providing considerable relief of otherwise intractable pruritus in a good proportion of PV patients.