Italian survey on clinical practice in myeloproliferative neoplasms. A GIMEMA Myeloproliferative Neoplasms Working Party initiative
Authors: Giuseppe G. Loscocco, Francesco Mannelli, Paola Guglielmelli, Chiara Paoli, Ilaria Marone, Rosalba Cucci, Giacomo Coltro, Benedetta Sordi, Francesco Albano, Massimo Breccia, Valerio De Stefano, Guido Finazzi, Alessandra Iurlo, Bruno Martino, Francesca Palandri, Francesco Passamonti, Sergio Siragusa, Lara Mannelli, Duccio Fantoni, Paola Fazi, Sergio Amadori, Marco Vignetti, Tiziano Barbui, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2019)

Classic myeloproliferative neoplasms (MPNs) are clonal disorders including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), primary MF (PMF) or post PV and post ET-MF. Important changes took place recently in the management of these neoplasms. The aim of this study, conducted as a web-based questionnaire, was to analyze the behavior of Italian hematologists directly involved in MPN patients, in particular how they face with guidelines and recommendations in a real-life setting. The GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Myeloproliferative Neoplasms Working Party e-mailed to 950 hematologists, belonging to 100 Italian hematology institutions, an anonymous online questionnaire (see Supporting Information) of 64 multiple-choice questions to survey aspects of diagnosis, risk stratification, management, and therapeutic options. One hundred-eighty hematologists (18.9%) declared to be routinely involved in MPN patients' management, and successfully completed the survey. Most practiced in University Hospital (61.7%), 35% in General Hospital and 3.3% in Private Hospital/practice setting. As many as 61.7% of respondents referred clinical experience in the field of MPNs since more than 10 years, 23.3% of 6 to 10 years, the remaining 13% for less than 5 years. For the diagnosis of PV, 95.6% of physicians routinely prescribe JAK2V617F genotyping, 74.6% erythropoietin levels, 47.5% bone marrow (BM) aspirate and biopsy. The proportion of patients with recent diagnosis of PV lacking a JAK2 genotype was less than 5% for 42.2% of respondents, while 45% declared that 100% of their patients labeled as PV had a positive JAK2V617F or exon 12 mutation tests. For diagnosis of ET, BM biopsy is performed routinely by 87.7% of respondents. In addition, 86.1% of physicians use a sequential approach where genotyping for JAK2V617F mutation is performed first followed, if absent, by CALR and MPL analysis; only 2% of respondents do not order molecular tests in subjects with thrombocytosis suspected to have ET. In the suspicion of PMF, 88.3% of respondents test for JAK2V617F, CALR and MPL mutation. Karyotype analysis at diagnosis is routinely ordered by 53.5% of physicians in the suspicion of PV, 55.6% for ET and 71.1% for MF. Concerning risk stratification, age > 60 and/or previous history of major vascular event is employed to define a high-risk condition by 97.9% of physicians; in ET, the same risk variables are used by 34% of physicians, while the international prognostic score in Essential Thrombocythemia (IPSET) score is used by 66%. In MF, international prognostic scoring system (IPSS) is used at diagnosis by 63.9% and dynamic international prognostic scoring system (DIPSS)/DIPSS-plus by 7.6%. During the follow-up, 52.8% and 20.8% use the DIPSS and DIPSS-plus, respectively, and 19.4% continue to use IPSS. Prognostically informative mutations comprising the high molecular risk (HMR) category in MF are routinely tested at diagnosis by 30.6% of physicians, by 15.3% during the follow-up and by 19.4%, to assess response to therapy (mainly, allogeneic hematopoietic stem cell transplantation, HSCT) although 81.7% of physicians do believe that HMR profile should be done in any young patient potential candidate to HSCT. However, MIPSS-70 score is currently applied used by only 4.9% and 6.9% of physicians at diagnosis and during follow-up. To reduce the expanded red blood cell mass in PV, 69.4% of respondents use a sex-independent hematocrit target at ≤45%, whereas 15.6% of physicians preferentially target to <42% for women. Phlebotomy is used by 82% of respondents as main therapeutic measure, while 18% perform regularly RBC-apheresis, with no difference in University and public or private hospitals. Cytoreduction is reserved to patients declared at high risk, however, about 50% of physicians use cytoreduction also in low risk patients for severe microvascular symptoms, systemic manifestations, uncontrolled thrombocytosis, leukocytosis, or splenomegaly; conversely, "difficulties" in controlling erythrocytosis with phlebotomies was considered an indication to cytoreduction in otherwise low-risk patients by a minority only (18.2%). Low-dose aspirin is recommended by 93.3% of physicians for all patients with PV irrespective of risk category. For patients with ET, low-dose aspirin is recommended routinely by 64.4% of physicians; considering those who do not prescribe prophylactic aspirin, 45% and 17.5% avoid aspirin in patients younger than 40 years and 60 years, respectively, and an additional 37.5% does not use aspirin in CALR mutated patients. In ET patients who present abnormally increased levels of hematocrit, 41.1% of respondents use a sex-independent hematocrit target at ≤45%, and 6.1% use the 42% threshold for women; 31.7% and 6.1% of respondents tolerate hematocrit levels at 45% to 50% and 50% to 55%, respectively. A total of 15% of respondents do not use phlebotomy at all in ET patients. The first, second, and third line cytoreductive therapy for PV and ET patients preferred by physicians are shown in Figure 1A,B. First line therapy to manage splenomegaly in MF patients is ruxolitinib for 57.2% of respondents followed by hydroxyurea (42.8%). As second line therapy, 47.8% of respondents use hydroxyurea, 45.6% ruxolitinib after hydroxyurea, and 6.7% other drugs (also in the context of clinical trials). First choice for managing drug refractory splenomegaly in MF patients previously treated with ruxolitinib is enrolment in clinical trials for 56.1% of respondents, splenectomy, and splenic irradiation for 21.7% and 22.2%, respectively. The agents used by physicians to treat MF associated anemia and thrombocytopenia are summarized in Figure 1C. Concerning HSCT, 72.4% and 49.2% of respondents consider it appropriate for IPSS/DIPSS high and intermediate-2 risk MF patients, respectively. An additional 19.3% of respondents consider HSCT also for intermediate-1 risk patients, while 14.9% consider it for all HMR patients MF patients, independent of IPSS/DIPSS category. Regarding MPN blast phase (MPN-BP), 37.8% of respondents have used palliation therapy only in more than 50% of the patients. When chemotherapy is considered an option for fit patients, the induction regimen used by 63.9% of physicians is the "7+3" scheme; dose-intensified induction regimens with high-dose of cytarabine with anthracyclines, or high doses cytarabine alone, are employed by 12.8% and 2.8% of respondents, respectively; other regimens (not specified) are used by 20% of respondents. Concerning repeating genetic testing during follow-up, the majority of respondents (83.8%) repeat measurement of the variant allele frequency (VAF) in case of remarkable changes in the clinical course, for example, if evolution to post PV-/post PET-MF is suspected. Also, 10.3% of physicians routinely assess VAF changes yearly, independent of treatment and clinical course, while 4.4% repeat the test in patients who receive interferon or ruxolitinib. As regarded repeating BM biopsies, the majority of respondents consider appropriate to reevaluate histopathology only if evolution to PPV-MF (93.9%) or PET-MF (95%) or progression to AML (95%) is suspected. We queried also about the approach used to evaluate splenomegaly. Most respondents use palpation (47.8%) and echo-scan (32.8%); only 12.2% and 2.8%, respectively, adopt computed tomography scan and magnetic resonance imaging. For assessing the symptom burden of patients with MPNs, only 19.4% of respondents use routinely MPN-SAF in their clinical practice, 38.3% use it occasionally while a 42.2% do not use it at all. To the best of our knowledge, this is the first comprehensive physician survey concerning all three classic MPNs; in fact, similar experience recently reported by Canadian, American, and German groups focused only on PV. We documented no substantial difference in practice between hospital- and academia-based Italian hematologists, indicating remarkable homogeneity over the country. Moreover, we found an overall high rate of abidance to diagnostic and therapeutic recommendations of international groups/agencies including the European Leukemia-Net (ELN),1 World Health Organization (WHO),2 European society for medical oncology (ESMO),3 and National Comprehensive Cancer Network (NCCN) (https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf). In particular, more than 90% of Italian hematologists routinely prescribe molecular tests to support diagnosis, according to WHO recommendations, similar to Canadian4 and academic American hematologists5 and higher than private hematologists from America5 and Germany.6 However, the survey also highlighted some areas of uncertainties, difficulties and possible improvement. Among these, we noticed that validated tools for serial measurement of patients' symptom burden, as the MPS-SAF, are still far from being routinely used in real life, in spite of their relevance for drug approval after controlled trials. Another aspect where we noted that performance of Italian hematologists resulted lower than expected according to guidelines regards the use of BM biopsy for diagnosis of PV. Owing to the high number of respondents, we believe this study offer a definitive picture of how MPNs are handled by Italian hematologists. However, we acknowledge that this kind of study does not necessary distinguishes between "daily practice" and "level of knowledge" by respondents; in other words, the remarkably high level of appropriateness of actions, according to guidelines and recommendations, might reflect the cultural level of respondents more closely than the actual application of such knowledge in practice. This kind of limitation could be eliminated only by controlled prospective studies, that are unfortunately very difficult to implement in practice. This work was supported by grants from GIMEMA ONLUS, Roma, and Associazione Italiana per le Leucemie (AIL), Sezione di Firenze. All authors declare no conflict of interest. G.G.L., F.M., P.G., A.M.V., designed the research, prepared the survey, analyzed the data, and wrote the manuscript. C.P., I.M., R.C., B.S., L.M., P.F., T.B., S.A., M.V. contributed to the survey development; F.A. M.B., V.D.S., G.F., A.I., B.M., F.P., S.S., D.F., collected data. All authors critically reviewed the manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.