COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and ...aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.
This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) ...consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.
To evaluate the cost-effectiveness of 12-month adjuvant trastuzumab therapy in women with high-risk human epidermal growth factor receptor 2 (HER2) -positive early breast cancer.
A Markov model ...tracked quarterly patients' transitions between five health states: disease free, local relapse, disease free after local relapse, metastatic disease, and death. Patients were allowed to incur symptomatic or asymptomatic transient cardiac dysfunction during trastuzumab administration. Probabilities were derived mainly from the combined report of the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 trials (95% node positive) and a meta-analysis by the Early Breast Cancer Trialists' Collaborative Group. Costs were estimated from the perspective of the Italian and US health care systems. The analysis was run during a 15-year time horizon. A 3% yearly discount rate was applied to both costs and life-years. Second-order Monte-Carlo and probabilistic sensitivity analyses were performed.
Adjuvant trastuzumab increases life expectancy by 1.54 (1.18 discounted) quality-adjusted life-years (QALYs). At a cost of 675 euros and 767 dollars per weekly dose in the Italian and US setting, respectively, trastuzumab achieves its clinical benefit at a cost of 14,861 euros (95% CI, 3,917 euros to 44,028 euros) and 18,970 dollars (95% CI, 6,014 dollars to 45,621 dollars) per QALY saved. The incremental cost effectiveness was higher than 50,000 euros/QALY (or 60,000 dollars/QALY) at time horizons shorter than 7.8 years and for patients older than 76 years or with a 10-year risk of relapse lower than 15%. The results confirmed the cost effectiveness when simulating a Herceptin Adjuvant Trial (HERA) -like scenario at multiway sensitivity analysis.
In a long-term horizon, adjuvant trastuzumab is a cost-effective therapy for patients with HER2-positive, high-risk, early breast cancer.
We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases (n = 647) were patients with second cancer ...(SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls (n = 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82-1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15-4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00-14.01), ruxolitinib (OR = 3.87, 95% CI 1.18-12.75), and for drug combination (OR = 3.47, 95% CI 1.55-7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.
Considerable data indicate post-transplant lenalidomide prolongs progression-free survival and probably survival after an autotransplant for multiple myeloma (MM). However, optimal therapy duration ...is unknown, controversial and differs in the EU and US. We compared outcomes and cost-effectiveness of 3 post-transplant lenalidomide strategies in EU and US settings: (1) none; (2) until failure; and (3) 2-year fixed duration. We used a Markov decision model, which included six health states and informed by published data. The model estimated the lenalidomide strategy given to failure achieved 1.06 quality-adjusted life years (QALYs) at costs
QALY gained of €29,232 in the EU and $133,401 in the US settings. Two-year fixed-duration lenalidomide averted €7,286
QALY gained in the EU setting and saved 0.84 QALYs at $60,835
QALY gained in the US setting. These highly divergent costs
QALY in the EU and US settings resulted from significant differences in post-transplant lenalidomide costs and 2nd-line therapies driven by whether post-transplant failure was on or off-lenalidomide. In Monte Carlo simulation analyses which allowed us to account for the variability of inputs, 2-year fixedduration lenalidomide remained the preferred strategy for improving healthcare sustainability in the EU and US settings.
In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In ...this study, we demonstrate that CLL cells from
-disrupted (
) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the
subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of
status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of
mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes
tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the
status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of
leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL.
Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an ...international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.
•In a case-control study, the frequency of thrombosis was higher in patients with MPN with second cancer than in matched MPN controls.•The occurrence of arterial thrombosis was associated with a twofold increased risk of carcinoma.
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The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of front-line, fixed-duration venetoclax and rituximab (VenR) in combination in young (≤65 years), fit patients with ...chronic lymphocytic leukemia and unmutated IGHV and/or TP53 disruption. Treatment consisted of the venetoclax ramp-up, six monthly courses of the VenR combination, followed by six monthly courses of venetoclax as a single agent. A centralized assessment of minimal residual disease (MRD) was performed by allele-specific oligonucleotide polymerase chain reaction assay on the peripheral blood and bone marrow at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range, 38-65), 96% had unmutated IGHV, 12% had TP53 disruption, and 4% had mutated IGHV with TP53 disruption. The overall response rate at the EOT was 94.7%, with a complete remission rate of 76%. MRD was undetectable in the peripheral blood of 69.3% of patients and in the bone marrow of 58.7% of patients. The 12-month MRD-free survival in the 52 patients with undetectable MRD in the peripheral blood at the EOT was 73.1%. After a median follow-up of 20.8 months, no cases of disease progression were observed. Three patients had died, two due to COVID-19 and one due to tumor lysis syndrome. The first report of the VERITAS study shows that front-line VenR was associated with a high rate of complete remissions and durable response with undetectable MRD in young patients with chronic lymphocytic leukemia and unfavorable genetic characteristics. ClinicalTrials.gov identifier: NCT03455517.
1 U.O. Ematologia e Centro Trapianti Cellule Staminali Emopietiche, Ospedale Oncologico Regionale "Armando Businco", Cagliari
2 Laboratorio di epidemiologia clinica, Fondazione IRCCS Policlinico ...S.Matteo, Pavia
3 Università Vita-Salute e IRCCS San Raffaele, Milano
4 Fondazione Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena IRCCS, Università di Milano
5 U.O. di Ematologia, Università di Pavia e Fondazione IRCCS Policlinico S. Matteo, Pavia
6 Ospedale Regionale Microcitemie, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari
7 Centro Microcitemie, Divisione di Ematologia Pediatrica, Dipartimento di Scienze Pediatriche, Università di Torino
8 Istituto di Ematologia ed Oncologia Medica "Seràgnoli", Università di Bologna, Italy
Correspondence: Emanuele Angelucci, MD, Hematology Department and BMT Unit, Cancer Center "Armando Businco", viale Edward Jenner, 09121 Cagliari, Italy. E-mail: emnang{at}tin.it
New measures of iron accumulation in liver and heart (superconducting quantum inference device and magnetic resonance imaging), and oral iron chelators (deferiprone and deferasirox) are available for managing iron overload in thalassemia major. To assure appropriate use of these new health technologies, the Italian Society of Hematology appointed a panel of experts to produce clinical practice-guidelines for the management of iron overload in thalassemia major and related disorders. The analytical hierarchy process, a technique for multicriteria decision analysis, was applied to relevant key questions in order to identify the alternative strategies, generate explicit criteria for their evaluation, and check how well the alternatives fulfilled the criteria. The result of a comprehensive systematic review of articles released from 1990 to 2007 was used as a source of scientific evidence to compare the decisional options pairwise, and select the final recommendation. Every step in the model was developed from questionnaires and group discussion. The resulting recommendations advise about which examination to carry out in order to plan iron chelation therapy, when to start iron chelation, which iron chelator to choose in regularly transfused patients, how to monitor iron chelation therapy, and when and how to switch standard therapy.
Key words: clinical practice guidelines, systematic review, thalassemia major, sickle cell anemia, deferoxamine, deferiprone, deferasirox.
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