New prognostic factors in primary myelofibrosis — a current state of knowledge

Pierwotne włóknienie szpiku to najgorzej rokujący wariant przewlekłych nowotworów mieloproliferacyjnych chromosom Filadelfia-ujemnych (ang. Philadephia-negative myeloproliferative neoplasms, MPN Ph-). Na chwilę obecną jedyną opcją leczniczą u chorych z mielofibrozą jest allogeniczne przeszczepienie krwiotwórczych komórek macierzystych. Procedura ta jednak obarczona jest dużą ilością powikłań i zarezerwowana jest tylko dla młodych chorych o ryzyku pośrednim-2 i wysokim wg. wskaźnika prognostycznego IPSS (ang. International Prognostic Scoring System IPSS). Lepsze poznanie patogenezy mielofibrozy umożliwiło stworzenie nowych leków (między innymi inhibitora JAK2 – Ruxolitynibu). Jednocześnie zaobserwowano, że nowo odkryte zaburzenia genetyczne są niezależnymi czynnikami rokowniczymi w mielofibrozie. W ostatnich latach powstało kilka nowych propozycji wskaźników prognostycznych. Wskaźniki te nadal nie są standardem postępowania, konieczne są badania celem weryfikacji ich skuteczności w lepszym definiowaniu grup ryzyka w mielofibrozie. Podstawowe pytanie w erze nowych leków to kiedy i u których pacjentów należy przeprowadzić allogeniczne przeszczepienie szpiku.Out of all Philadelphia-negative myeloproliferative neoplasms, primary myelofibrosis has the worst prognosis. Currently, an allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative method for patients with primary myelofibrosis. This procedure however bears a high risk of complications and is reserved for only those patients with short overall survival. The development of new drugs (ruxolitynib amongst others) was made possible thanks to an improved understanding of the pathogenesis of primary myelofibrosis. It was also observed that newly discovered genetical abnormalities constituted independent risk factors in patient with primary myelofibrosis. Furthermore, a few new proposals of risk prognostic scores have been developed. These risk scores are still not a gold standard and new studies are required to verify their use whenever risk groups have been better defined in primary myelofibrosis patients. In the new drug era, the main question is which patients should now receive allo-HSCT

Mixed phenotype acute leukemia and lineage switch from lymphoblastic leukemia to myeloid leukemia in the course of Philadelphia-negative myeloproliferative neoplasm – case reports and literature review

Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs) are characterized by clonal hematopoiesis derived from a mutated hematopoietic stem cell. Ph-neg MPNs rarely transforms into acute leukemia, and in most cases, the transformation leads to the development of acute myeloid leukemia (AML). The incidence of mixed-phenotype leukemia (MPAL) or acute lymphoblastic leukemia (ALL) with lineage switch is much rarer. The unidentified lineage of blast cells is due to the immaturity of their undifferentiated progenitors with co-expression of myeloid and lymphoid antigens. The prognosis of secondary acute leukemia transformed from Ph-neg MPN is very unfavorable, especially in MPAL or lineage switch from ALL to AML cases. Moreover, there are no therapeutic protocols for these specific leukemia subtypes. Therefore, we believe that all cases of MPAL or lineage switch leukemia should be reported. This article presents the case of a patient with JAK2-positive essential thrombocythemia (ET) transformed to MPAL, and a patient with triple-negative primary myelofibrosis (PMF) (negative for , , and ) transformed to ALL with subsequent lineage switch to AML

Nowotwór nerki u pacjentów ze szpiczakiem plazmocytowym — opis dwóch przypadków i przegląd piśmiennictwa

Multiple myeloma (MM) is characterized by malignant spreading of monoclonal plasma cells in bone marrow. Renal cell carcinoma (RCC) is a result of neoplastic proliferation of epithelial cells in nephron proximal convoluted tubule and forms 95% of malignant kidney’s neoplasms. There are some reports about coexistence of MM and RCC but it is a rare phenomenon. We describe two cases of patients in which during the therapy of MM, RCC was detected accidentally. Radical nephrectomy in early stage of RCC allowed complete recovery and did not interrupt the continuation of MM’s therapy. Additionally, similar cases from literature are discussed.Szpiczak plazmocytowy (PCM) charakteryzuje się ekspansją nowotworowych komórek plazma­tycznych w szpiku. Rak nerkowokomórkowy (RCC) jest rezultatem złośliwej proliferacji komórek nabłonkowych kanalików proksymalnych nefronu i stanowi 95% złośliwych nowotworów nerki. Współistnienie PCM i RCC to zjawisko bardzo rzadkie, istnieją jedynie pojedyncze doniesienia na ten temat. W pracy przedstawiono opis dwóch chorych, u których w trakcie terapii PCM wykryto przypadkowo RCC. Radykalna nefrektomia (we wczesnej fazie choroby) umożliwiła całkowite wyleczenie RCC i kontynuację terapii PCM. Ponadto w artykule omówiono podobne przypadki opisane w literaturze

Breakthrough infections in MPN-COVID vaccinated patients

Myeloproliferative diseaseEnfermedad mieloproliferativaMalaltia mieloproliferativaThe study was supported by a research grant by the COVID “3 × 1 project”, BREMBO S.p.A., Bergamo, Italy (T.B.) and by AIRC 5 × 1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at https://progettomynerva.it (A.M.V., P.G.). The study was also supported by HARMONY PLUS, which is funded through the Innovative Medicines Initiative (IMI), Europe’s largest public–private initiative aiming to speed up the development of better and safer medicines for patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe

Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments

Inflammation-related molecules in tears of patients with chronic ocular pain and dry eye disease

Producción CientíficaThe purpose of this study was to analyze inflammation- and pain-related molecules in tears of patients suffering from chronic ocular pain associated with dry eye (DE) and/or a previous corneal refractive surgery (RS). Based on history, symptomatology, and clinical signs, the subjects (n = 180, 51.0 ± 14.7 years, 118 females, 62 males) in this cross-sectional study were assigned to one of five groups: DE and chronic ocular pain after RS (P/DE-RS, n = 52); asymptomatic subjects, i.e., without DE and chronic ocular pain, after RS (A-RS, n = 30); DE and chronic ocular pain without previous RS (P/DE-nonRS, n = 31); DE, no pain, and no previous RS (DE-nonRS, n = 35); and asymptomatic subjects with no previous RS (controls, n = 32). The tear concentrations of 20 cytokines and substance P (SP) were analyzed by immunobead-based assay and enzyme-linked immunosorbent assay, respectively. We found that tear levels of interleukin (IL)-10 and SP were increased in the RS groups. There were significant differences in IL-8/CXCL8 among the five groups. Nerve growth factor (NGF) tear levels were significantly higher in P/DE-RS than in DE-nonRS and controls. IL-9 had the highest percentage of detection in the P/DE-RS and P/DE-nonRS groups, while macrophage inflammatory protein (MIP)-1α, IL-2, and interferon (IFN)-γ were higher in the P/DE-RS, A-RS, and P/DE-nonRS groups. IL-17A was detected only in the A-RS group. Moderate correlations were observed in the A-RS, P/DE-nonRS, DE-nonRS and controls groups. A positive correlation was obtained between growth related oncogene concentration and tear break-up time (rho = 0.550; p = 0.012), while negative correlation was found between monocyte chemoattractant protein-3/CCL7 and conjunctival staining (rho = −0.560; p = 0.001), both in the A-RS group. IL-10 correlated positively with ocular pain intensity (rho = 0.513; p = 0.003) in the P/DE-nonRS group. Regulated on Activation Normal T Cell Expressed and Secreted/CCL5 correlated negatively with conjunctival staining (rho = −0.545; p = 0.001) in the DE-nonRS group. SP correlated negatively with corneal staining (rho = −0.559; p = 0.001) in the controls. In conclusion, chronic ocular pain was associated with higher IL-9 tear levels. IL-10, SP, MIP-1α/CCL3, IL-2, and IFN-γ were associated with previous RS. Higher levels of IL-8/CXCL8, MIP-1α/CCL3, IL-2, and IFN-γ were associated with DE-related inflammation, while NGF levels were related to chronic ocular pain and DE in RS patients. These findings suggest that improved knowledge of tear cytokines and neuromodulators will lead to a more nuanced understanding of how these molecules can serve as biomarkers of chronic ocular pain, leading to better therapeutic and disease management decisions.Ministerio de Ciencia, Innovación y Universidades (grants SAF-2016-77080-P, FPU17/02715 and FPU15/01443

Zaawansowana mastocytoza układowa — stanowisko ekspertów dotyczące postępowania diagnostycznego i leczniczego

Systemic mastocytosis (SM) is characterized by clonal proliferation of abnormal mast cells and their accumulation in skin and/or other organs. The annual incidence of SM is between 5–10 new cases per million population and it usually occurs above 30 years of age. The diagnostic criteria include the detection of aggregates of mast cells in bone marrow, an increased serum tryptase level, the expression of CD25 on the mast cells and the presence of somatic mutation within the KITD816V. An advanced SM encompasses three variants with which hematologists should be familiar with 1) aggressive SM (ASM), 2) SM with an associated hematological neoplasm (SM-AHN) and 3) mast cell leukemia (MCL). Among them MCL has the worst prognosis with median survival of 2 months. The prognostic factors in SM include both clinical, laboratory and molecular parameters, but the latter are of special interest. The adverse prognosis is associated with the mutations within the genes: SRSF2, RUNX1 and ASXL1. The therapeutic approach independently from SM variant, should be aimed at avoidance of known triggers of mast cell activation and anti-mediator therapy as needed. Midostaurin with overall response rate of 60% should be the first-line choice when the symptoms of organ dysfunction occurs. The other treatments comprise cladribine and [peg]interferon alpha. The only curative therapy for SM is allogeneic stem cell transplantation. In this manuscript we present the current views on diagnostic and therapeutic approach for patients with this rare entity.Układowa mastocytoza (SM) charakteryzuje się klonalną proliferacją nieprawidłowych komórek tucznych (mastocytów) i ich gromadzeniem w skórze lub innych narządach. Choroba ta występuje z częstością 5–10 przypadków na 1 mln populacji rocznie, zwykle u osób powyżej 30. roku życia. Kryteria rozpoznania choroby obejmują obecność skupisk komórek tucznych w szpiku kostnym, zwiększone stężenie tryptazy w surowicy, wykazanie ekspresji CD25 na komórkach tucznych oraz obecność mutacji KITD816V. W skład zaawansowanych układowych mastocytoz wchodzą i w kręgu zainteresowań hematologa pozostają następujące warianty 1) agresywna układowa mastocytoza; 2) układowa mastocytoza z towarzyszącym nowotworem hematologicznym (SM-AHN) oraz 3) białaczka z komórek tucznych (MCL). Spośród wymienionych najmniej korzystne rokowanie występuje u chorych na MCL (mediana przeżycia 2 miesiące). Czynniki prognostyczne SM obejmują zarówno parametry kliniczne, laboratoryjne jak i molekularne, a spośród tych ostatnich niekorzystne są mutacje w obrębie genów SRSF2, RUNX1 i ASXL1. Postępowanie terapeutyczne, niezależnie od wariantu SM, powinno obejmować unikanie czynników wyzwalających aktywację komórek tucznych oraz leczenie objawów zależnych od mediatorów, jeśli jest taka potrzeba. W przypadku wystąpienia cech uszkodzenia narządowego zależnego od nacieku komórkami tucznymi lekiem pierwszego wyboru powinna być midostauryna, która wykazuje skuteczność u około 60% pacjentów. Inne możliwości terapeutyczne obejmują kladrybinę i [peg]interferon alfa. Jedynym sposobem wyleczenia SM jest przeszczepienie allogenicznych krwiotwórczych komórek macierzystych. W pracy przedstawiono aktualne poglądy na proces diagnostyczny i leczniczy tej rzadkiej jednostki chorobowej

Outcome of older (≥70 years) APL patients frontline treated with or without arsenic trioxide-an International Collaborative Study

Data on outcome in older (≥70 years) patients with acute promyelocytic leukemia after treatment with arsenic trioxide (ATO) compared with standard chemotherapy (CTX) is scarce. We evaluated 433 patients (median age, 73.4 years) treated either with ATO+ all-trans retinoic acid (ATO/ATRA; n = 26), CTX/ATRA + ATO during consolidation (CTX/ATRA/ATO; n = 148), or with CTX/ATRA (n = 259). Median follow-up for overall survival (OS) was 4.8 years. Complete remissions (CR) were achieved in 92% with ATO/ATRA and 82% with CTX/ATRA; induction death rates were 8% and 18%, respectively. For analysis of postremission outcomes we combined the ATO/ATRA and CTX/ATRA/ATO groups (ATO/ATRA ± CTX). Cumulative incidence of relapse (CIR) was significantly lower after ATO/ATRA ± CTX compared with CTX/ATRA (P 10 × 10 9 /l) white blood cell (WBC) counts at diagnosis were associated with higher CIR (P < 0.001) compared with lower WBC in the CTX/ATRA group, but not in the ATO/ATRA ± CTX group (P = 0.48). ATO, when added to ATRA or CTX/ATRA is feasible and effective in elderly patients for remission induction and consolidation, particularly in patients with high WBC at diagnosis