Conditioning Regimens for Frail Patients with Acute Leukemia Undergoing Allogeneic Stem Cell Transplant: How to Strike Gently.

Despite the recent dramatic progress in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) therapy, allogeneic transplant remains a mainstay of treatment for patients with acute leukemia. The availability of novel compounds and low intensity chemotherapy regimens made it possible for a significant proportion of elderly and comorbid patients with AML or ALL to undergo curative treatment protocols. In addition, the expansion of donor availability and the recent dramatic progress in haploidentical stem cell transplant, allow the identification of an available donor for nearly every patient. Therefore, an increasing number of transplants are currently performed in elderly and frail patients with AML or ALL. However, allo-Hematopoietic stem cell transplant (HSCT) in this delicate setting represents an important challenge, especially regarding the selection of the conditioning protocol. Ideally, conditioning intensity should be reduced as much as possible; however, in patients with acute leukemia relapse remains the major cause of transplant failure. In this article we present modern tools to assess the patient health status before transplant, review the available data on the outcome of frail AML an ALL patients undergoing allo-HSCT, and discuss how preparatory regimens can be optimized in this setting.

Clinical research and burnout syndrome in Italy - only a physicians' affair?

BACKGROUND: The burnout phenomenon has been extensively investigated among health care professionals, particularly focusing on physicians and nurses. However, literature concerning burnout in clinical research is poor and often neglects the other professional categories involved. METHODS: In March 2019, all members of Italian Group of Clinical Research Coordinator were invited to participate to a web survey, consisting of three sections: general information and workload; Maslach Burnout Inventory (MBI) test; subjective perception of oneself's work stress and possible causes. RESULTS: The majority of respondents felt a form of distress. The main source was contract type (31.2%), followed by workload (20.5%) and lack of skills recognition (17.8%). Results from MBI test confirmed the interviewees' subjective perception: an intermediate level of emotional exhaustion (19.1 points) and a very high sense of reduced professional achievement (26.8 points) were observed. Both depersonalization and sense of reduced professional achievement showed weak to moderate correlations with emotional exhaustion. Emotional exhaustion was associated with contract type with high significance. CONCLUSION: It is necessary to act on those qualitative factors that are greatly increasing the level of perceived stress, jeopardizing the quality of clinical research coordinators work and significantly amplifying the phenomenon of migration towards the private sector.

Severe COVID-19 in a patient with chronic graft-versus-host disease after hematopoietic stem cell transplant successfully treated with ruxolitinib.

Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplant, which is known to be mediated by cytotoxic T-cell effectors and dysregulated inflammatory cytokines. Similarly, the lung injury observed in severe COVID-19 cases appears to be related to a massive production of pro-inflammatory cytokines. The selective JAK1/2 inhibitor ruxolitinib has shown promising results in the context of GVHD, and different trials are currently underway in patients with severe COVID-19; nevertheless, no clinical observation of safety or efficacy of treatment with ruxolitinib in this context has been published yet. We describe a first case of severe COVID-19 developed after hematopoietic stem cell transplantation in a patient with a concomitant chronic GVHD (cGVHD), in which a treatment with ruxolitinib was administered with good tolerance and positive outcome.

[Clinical research: enough players to get out there?] / Ricerca clinica: abbastanza giocatori per vincere la partita?

Despite the presence of experienced and multidisciplinary staff is now essential due to the increasing complexity of clinical research, many national collective health contracts do not yet contemplate the new professional figures. This instability risks causing an alarming professional gap, especially for non-profit clinical research. For this reason, we would try to evaluate the extent to which the problem is widespread among Italian clinical research coordinators, verifying how much the Italian institutes have permanently integrated this professional figure into organic plant, through stable and specific employment contracts. In November 2016, when the Italian Government has declared for the first time its intention to prevent further renewal of contracts with atypical employment, we conducted a survey with the intent of mapping the extent of the contractual issues related to the figure of the clinical research coordinator. Two years later, we repeated the survey to see if something was changed and if it was any improvement in the employment situation. In November 2016, only a small fraction of the respondents (13.8%) was hired with a permanent contract, while the majority (73.2%) were employed with an atypical one. Regarding the impossibility to renew the atypical contracts due to the new Government provisions starting from January 2017: the 67.5% of the respondents stated that the issue would directly affect him. Two years later, the situation looks even worse: only the 11.5% of the respondents are hired on a permanent contract, while there is a very high percentage (74.8%) of atypical contracts, with even some coordinators who say they have been working for several months as unpaid volunteers. It is interesting to note that over 30% of staff with atypical contracts work in research institutes and research-related scientific societies, with a strong interest in non-profit clinical research. Adopt Clinical Trials Units officially and contractually recognized would be essential to bring back our nation on the top of the world health systems ranking, but yet the Italian research-dedicated infrastructures continue to be a ghost reality, deeply characterized by a continuous professional turnover and by the lack of long-term prospects. In the absence of a permanent solution, Italy is unlikely to reach the required standards, denying patients of possible therapeutic available options. Our non-profit research will pay the most for it.

[Clinical research coordinators: a crucial resource.] / Coordinatori di ricerca clinica: una risorsa indispensabile.

The increasing complexity that characterizes the world of clinical trials, both in terms of procedures and bureaucracy, has made it necessary to create dedicated infrastructures composed of experienced and qualified personnel, who constantly work to ensure high ethical and qualitative standards. A key role in these infrastructures is played by the clinical research coordinator, a key figure able to manage the workflow required, placing himself as a reference for the coordination of the various activities and professional figures involved. The literature has widely demonstrated how the presence of this professional figure is a valid contribution both from a documentary and administrative point of view as well as a crucial resource for what concerns the indicators of ethics and quality of research. Despite that, there is no yet an institutional recognition of the professional figure, neither a specific economical agreement within the National Health System. The lack of institutional recognition is causing a worrying phenomenon of migration of qualified personnel towards contract research organizations and pharmaceutical companies. That could be detrimental to the competitiveness of Italian clinical research and hinder the possibility of offering innovative experiments therapies to patients, with serious ethical consequences.

A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi.

BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P < .001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P = .017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P < .001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P < .001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM = .1 versus FEAM = .19, P < .001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P = .42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P = .04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.

Results of a prospective phase II trial with oral low-dose bexarotene plus photochemotherapy (PUVA) in refractory and/or relapsed patients with mycosis fungoides.

INTRODUCTION: Bexarotene is a synthetic retinoid effective in early and advanced stages of mycosis fungoides (MF)/Sezary Syndrome (SS) both in monotherapy and combination schemes. We aimed to assess disease response to low-dose bexarotene and PUVA in maintenance in refractory and/or resistant patients with early and advanced stage MF/SS. METHODS: We followed prospectively 21 patients (stages IB-IV): 15 with early stage MF and 6 with advanced disease. "Mini" and standard protocols were respectively applied to patients who failed PUVA or several systemic regimens. The dose of bexarotene and the administration of PUVA were titrated individually and tailored during induction and maintenance according to previous therapy, disease stage and toxicity. We evaluated overall response (OR) at the end of maintenance, safety and event-free survival (EFS). RESULTS: After induction phase, OR was 85.6%, higher in early MF (93.4%) than in advanced disease (66.6%). At the end of maintenance, OR was 76.2%, including 33.3% of CR. Median EFS for the whole group was 31 months. Bexarotene was well tolerated regarding the side effects, with prophylaxis and progressive drug increase in the induction phase of the protocol. Side effects were mainly of low and moderate grades. CONCLUSIONS: We observed a favorable rate of therapeutic effects and few, generally mild, side effects with low doses of bexarotene combined with PUVA.

Thrombosis in essential thrombocytemia and early/prefibrotic primary myelofibrosis: the role of the WHO histological diagnosis.

BACKGROUND: Vascular events represent the most frequent complications of thrombocytemias. We aimed to evaluate their risk in the WHO histologic categories of Essential Thrombocytemia (ET) and early Primary Myelofibrosis (PMF). METHODS: From our clinical database of 283 thrombocytemic patients, we selected those with available bone marrow histology performed before any treatment, at or within 1 year from diagnosis, and reclassified the 131 cases as true ET or early PMF, with or without fibrosis, according to the WHO histological criteria. Vaso-occlusive events at diagnosis and in the follow-up were compared in the WHO-groups. RESULTS: Histologic review reclassified 61 cases as ET and 72 cases as early PMF (26 prefibrotic and 42 with grade 1 or 2 fibrosis). Compared to ET, early PMF showed a significant higher rate of thrombosis both in the past history (22% vs 8%) and at diagnosis (15.2% vs 1.6%), and an increased leukocyte count (8389 vs 7500/mmc). Venous thromboses (mainly atypical) were relatively more common in PMF than in ET. Patients with prefibrotic PMF, although younger, showed a significant higher 15-year risk of developing thrombosis (48% vs 16% in fibrotic PMF and 17% in ET). At multivariate analysis, age and WHO histology were both independent risk-factors for thrombosis during follow-up; patients >60 yr-old or with prefibrotic PMF showed a significantly higher risk at 20 years than patients <60 yr-old with ET or fibrotic PMF (47% vs 4%, p = 0.005). CONCLUSIONS: Our study support the importance of WHO histologic categories in the thrombotic risk stratification of patients with thrombocytemias. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2020211863144412 .