Inhibitory JAK — czy jesteśmy świadkami przełomu w leczeniu włóknienia szpiku?

Primary myelofibrosis (PMF), a myeloproliferative neoplasm, is manifested by anemia,leukoerythroblastosis in peripheral blood and extramedullary hematopoiesis. Consitutionalsymptoms that result from massive splenomegaly and elevated levels of serum proinflammatorycytokines are present in some MF cases. 50–60% of patients with myelofibrosis (MF) werefound to have a JAK2V617F point mutation, however dysregulation of JAK-STAT signalpathway may play a central pathogenic role in MF, regardless of the mutational status of JAK2.The above-mentioned discovery provided an impetus to the development of JAK inhibitors andruxolitinib was the first approved in November 2011 by the Food and Drug Administration forthe treatment of patients with intermediate and high risk myelofibrosis. Ruxolitinib and other JAK inhibitors currently in clinical trials, are found to alleviate constitutional symptoms andreduce the spleen volume, but have yet to reverse bone marrow fibrosis as well as to improvesurvival over best available treatment. Their increased use may be restricted by side effectsparticularly anemia and thrombocytopenia. This review presents current data and perspectiveof JAK inhibitors; we discussed in details the recently published studies COMFORT-1 andCOMFORT-2 which became the background for ruxolitinib approval.Pierwotne włóknienie szpiku (PMF) jest nowotworem mieloproliferacyjnym, który objawia sięniedokrwistością, leukoerytroblastozą we krwi obwodowej i hematopoezą pozaszpikową. U częścichorych występują objawy ogólne, które są związane z występowaniem znacznej splenomegaliii zwiększonego stężenia cytokin prozapalnych w surowicy. U 50–60% chorych z włóknieniemszpiku (MF) wykrywa się obecność mutacji punktowej JAK2V617F, jednak dysregulacja drogisygnałowej JAK-STAT stanowi istotę patogenezy MF, niezależnie od statusu mutacji JAK2.Powyższe odkrycie stanowiło impuls do rozwoju inhibitorów JAK, spośród których ruksolitynibjako pierwszy, w listopadzie 2011 roku, uzyskał akceptację Food and Drug Administration doleczenia chorych z MF o pośrednim i wysokim stopniu ryzyka. Ruksolitynib oraz inne inhibitoryJAK będące w fazie badań klinicznych powodują zmniejszenie objawów konstytucjonalnychi znaczną redukcję wielkości śledziony, natomiast nie odwracają włóknienia szpiku, jak równieżnie wydłużają przeżycia w porównaniu z najlepszym obecnie dostępnym leczeniem. Ichszersze zastosowanie może być ograniczone przez działania niepożądane, zwłaszcza niedokrwistośći małopłytkowość. W pracy przedstawiono obecny stan wiedzy i perspektywy leczeniainhibitorami JAK; szczegółowo omówiono niedawno opublikowane wyniki badań COMFORT-1i COMFORT-2, które stały się podstawą do rejestracji ruksolitynibu

How to manage cytomegalovirus reactivation/infection after hematopoietic stem cell transplantation: practical tips for clinicians

Cytomegalovirus (CMV) reactivation is one of the most common and life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is associated with an increased risk of transplantation failure, non-relapse mortality (NRM), and lower overall survival (OS) than in patients without CMV reactivation, even in the era of pre-emptive antiviral treatment. Numerous risk factors for CMV reactivation in the setting of allo-HSCT have been identified. Donor/recipient CMV serological status remains the main risk factor influencing the incidence and mortality of CMV disease after transplantation. Proper selection of donor and recipient, regular and careful monitoring, an early intervention in CMV reactivation, and rapid and effective treatment when the disease develops, remain crucial to decrease the risk of post-transplantation CMV reactivation/disease. The introduction of letermovir as CMV prophylaxis has reduced NRM and improved OS. Herein we present practical tips as to how to manage CMV reactivation/disease after allo-HSCT through an illustrative case report, with a focus on the risk factors present before and during the procedure

How we manage the patient with hypereosinophilic syndrome?

Hypereosinophilic syndrome (HES) is a group of rare disorders characterized by marked and persistent blood hypereosinophilia and documented as an eosinophilia-attributable organ impairment. Discovery of some novel genetic abnormalities let to the categorization of HES patients into a common group of myeloid and lymphoid neoplasms with eosinophilia and recurrent gene rearrangements: platelet-derived growth factor receptor α and β (PDGFRA/B) and fibroblast growth factor receptor 1 (FGFR1). This classification, however, differs from that one proposed by Working Group for Eosinophilic Disorders in 2012. Namely, HES patients were divided into 3 variants: idiopathic, myeloproliferative (including cases with well-known gene rearrangements) and reactive (including lymphocytic HES). Despite the progress in diagnostic approach, especially in molecular testing, a vast majority of HES cases remain idiopathic. Except the PDGFRA/B-positive patients where tyrosine kinase inhibitor – imatinib mesylate – remains a treatment of choice, the therapy for other HES variants is somehow similar and includes steroids, hydroxyurea and interferon. The PDGFRA/B-positive population has an excellent prognosis with complete hematologic and molecular remissions achieved as 100% and >95% in imatinib-treated patients, respectively. The estimated probability of survival at 20 years for strictly defined idiopathic HES is found to be around 70%. The worst prognosis was demonstrated for cases with chronic eosinophilic leukemia – not otherwise specified and those with FGFR1 rearrangements. This review presents the current state of knowledge on definitions, classifications and treatment of HES in the molecular era

Thrombotic complications in Philadelphia-negative myeloproliferative neoplasms

Powikłania zakrzepowe są często obserwowane u chorych z czerwienicą prawdziwą (PV) i nadpłytkowością samoistną (ET) i stanowią główną przyczynę zgonów w tych jednostkach chorobowych. W układzie żylnym mogą się objawiać jako żylna choroba zakrzepowo-zatorowa, często jednak lokalizują się w miejscach nietypowych. W łożysku tętniczym zakrzepy są najczęściej zlokalizowane w naczyniach wieńcowych, w tętnicach krezkowych oraz w tętnicach mózgowia. U chorych z pierwotnym włóknieniem szpiku (PMF) obserwuje się także zwiększone ryzyko powikłań zakrzepowych. W PV/ET/PMF ryzyko jest zwiększone u pacjentów powyżej 60. roku życia oraz po przebytym epizodzie zakrzepowym. Spośród innych analizowanych czynników znaczenie wydają się mieć liczba leukocytów w momencie rozpoznania (u chorych z PV/ET) oraz obecność mutacji JAK2V617F (w PV/ET/PMF). W pracy przedstawiono aktualne poglądy dotyczące czynników sprzyjających występowaniu zakrzepicy, a także omówiono prawdopodobny patomechanizm powikłań.Thrombotic complications are frequently observed in patients with polycythemia vera (PV) and essential thrombocythemia (ET). They remain a main cause of mortality in a majority of above mentionedpatients. In venous system, thrombosis may manifest as venous thromboembolism as well as it may affect veins of unusual locations. In arterial system, it involves coronary, mesenteric and cerebral vessels. Patients with primary myelofi brosis (PMF) were found to have an increased risk of thrombotic complications as well. It was demonstrated that the risk of thrombosis is increased in patients older than 60 years and with a history of thrombotic episode. The other risk factors mayinclude leukocyte count at diagnosis (in PV/ET) and the presence of JAK2V617F point mutation (PV/ET/PMF). Our paper presents the current views on factors infl uencing the development of thrombosis. The probable pathomechanism of thrombosis has also been discussed

Targeted therapy and allogeneic hematopoietic stem cell transplantation may cure patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disorder with a diverse prognosis. About 70% of AML patients may achieve complete remission after conventional chemotherapy, but long-term outcome remains unsatisfactory. The development of molecular biology resulted in a better understanding of AML pathogenesis as well as it allowed us the introduction of targeted therapy. However, most AML patients still require the allogeneic hematopoietic stem cell transplantation (alloHSCT) to be cured. The long-term results of alloHSCT for AML depend on a variety of factors including the age at transplant, the presence of well-defined risk factors and disease status at transplant. It seems that the combination of targeted therapy with conventional chemotherapy and subsequent alloHSCT may be a chance for curing a significant proportion of AML patients

A living drug: application of CAR-T therapy for lymphoid malignancies and beyond

The ongoing development of novel personalized cancer therapies has resulted in the implementation of T cells enriched with synthetic chimeric antigen receptors, known as chimeric antigen receptors T cell (CAR-T) cells, into clinical practice. CAR-T cells are able to recognize and bind specific antigens present on the surface of target cells — so-called tumor-associated antigens. This innovative method has been approved for the treatment of hematological malignancies and may also serve as a bridge to hematopoietic stem cell transplantation. The production of the drug containing modified T cells consists of several steps — leukapheresis, T cell activation, transduction and expansion of the final CAR-T cells. Activation of CAR-T cells occurs through a pathway independent of the major histocompatibility complex, which is often associated with uncontrolled responses from the immune system and adverse reactions such as cytokine release syndrome. CAR-T therapy can only be performed in certified centers, and requires close cooperation between experienced specialists of different medical disciplines. This is what determines its effectiveness. Every step from collection and cryopreservation, through transport and modification, to thawing and infusion is strictly controlled because it has a critical impact on the quality and efficiency of the drug. Despite its proven benefits, CAR-T therapy remains available only to patients who meet well-defined criteria. These however are liable to change with the emergence of new indications

Infection-related hemophagocytic lymphohistiocytosis – a case report

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disorder characterized by abnormal activation of macrophages. It is also characterized by hemophagocytosis in the bone marrow and in the reticuloendothelial system (RES). The most common symptoms are persistent fever, splenomegaly and cytopenia. The probable mechanism of disease is due to hyperinflammation caused by increasing amounts of proinflammatory cytokines. As a consequence numerous metabolic disturbances with multiple organ failure occur. Without a proper treatment this disease may have a fatal outcome. Herein we present a 24-year-old male with HLH who achieved a rapid response to the therapy despite the initial poor overall condition which was associated with an advanced disease stage as well as prolonged diagnostic process