Μελέτη των διαταραχών πήξης σε νεοδιαγνωσθέντες ασθενείς με λέμφωμα Hodgkin

Το λέμφωμα Hodgkin είναι μια σχετικά σπάνια κακοήθης νόσος του λεμφικού συστήματος με καλή πρόγνωση και ασυνήθιστα ιδιαίτερη βιολογία. Η ιδιαιτερότητα αυτή έγκειται στο γεγονός ότι τα χαρακτηριστικά κύτταρα Hodgkin-Reed-Sternberg αποτελούν μόλις το 1% της μάζας του λεμφώματος, ενώ το υπόλοιπο αποτελείται από τα κύτταρα του μικροπεριβάλλοντος, τα οποία είναι κυρίως λεμφοκύτταρα, ηωσινόφιλα, ουδετερόφιλα, μακροφάγα κλπ. Η σύσταση του μικροπεριβάλλοντος διαφοροποιείται και χαρακτηρίζει τους ιστολογικούς υπότυπους του HL και παίζει καθοριστικό ρόλο στην πολύπλοκη παθογένεση της νόσου. Χαρακτηριστικό γνώρισμα της νόσου είναι η ύπαρξη κλινικοεργαστηριακού φλεγμονώδους συνδρόμου, του οποίου η έκταση συμβαδίζει με τα προχωρημένα στάδια και την παρουσία Β-συμπτωμάτων. Έτσι, παρατηρείται αύξηση των συνήθων δεικτών φλεγμονώδους δραστηριότητας, όπως η ταχύτητα καθίζησης των ερυθρών αιμοσφαιρίων (ΤΚΕ), η C- αντιδρώσα πρωτείνη (CRP), το ινωδογόνο, οι απτοσφαιρίνες, η φερριτίνη, οι α2- και γ- σφαιρίνες, συχνά ελάττωση της αιμοσφαιρίνης και της αλβουμίνης, καθώς και αύξηση των λευκών αιμοσφαιρίων και των αιμοπεταλίων. Με αφορμή την παρατήρηση μας στην κλινική πράξη, ότι ασθενείς με HL συχνά εμφανίζουν κατά τη διάγνωση διαταραχές του αιμορραγικού ελέγχου και δεδομένου του γεγονότος ότι οι διαταραχές αυτές δεν έχουν επισήμως περιγραφεί στη βιβλιογραφία, ιδίως σε συγγράμματα αναφοράς, θελήσαμε να αποτυπώσουμε αυτό το φαινόμενο και να μελετήσουμε πιθανούς υποκείμενους παθογενετικούς μηχανισμούς. Έτσι, συγκεντρώσαμε και μελετήσαμε δείγματα ορού και πλάσματος από 35 ασθενείς με αρχική διάγνωση HL που προσήλθαν στο Κέντρο μας κατά τη χρονική περίοδο από 2ο/2018 έως 2ο/2019, προ της χορήγησης θεραπείας. Πράγματι, φάνηκε ότι το 29% των ασθενών αυτών παρουσιάζουν παράταση του χρόνου προθρομβίνης (PT)/INR (>1.2) και το 37% του χρόνου ενεργοποιημένης μερικής θρομβοπλαστίνης (aPTT) (>40 sec), η οποία είναι πλέον έκδηλη στα προχωρημένα στάδια της νόσου και σε ασθενείς με Β-συμπτώματα. Επιπλέον, διαπιστώθηκαν αυξημένα επίπεδα D-Dimers (>0.5 μg/ml) στο 58% των ασθενών, τα οποία συσχετίζονταν με τον υψηλό IPS (≥3). Στην προσπάθεια διερεύνησης πιθανού παθογενετικού μηχανισμού μετρήθηκε η ενεργότητα των παραγόντων II, V, VII, X και τα επίπεδα του TFPI. Παρατηρήθηκε αρνητική συσχέτιση του PT με τον FVII, ενώ δεν προέκυψε κάποια συσχέτιση του PT/INR με τον TFPI. Ο TFPI ανευρέθηκε αυξημένος στο 66% των ασθενών. Επιπλέον παρατηρήθηκαν αυξημένες τιμές ενεργότητας των παραγόντων II, V και X και συσχέτιση αυτών με τις εργαστηριακές παραμέτρους που αντανακλούν το φλεγμονώδες σύνδρομο. Συμπερασματικά, φάνηκε η παράταση του PT/INR και του aPTT να αποτελούν συμπαρομαρτούντα ευρήματα που αποδίδονται στην ενεργότητα της νόσου και να επισυμβαίνουν λόγω υπέρμετρης ενεργοποίησης του μηχανισμού της αιμόστασης στα πλαίσια του φλεγμονώδους συνδρόμου στο HL. Στα ίδιο πλαίσιο εξηγείται και η αύξηση των παραγόντων II, V και X, γεγονός όμως που φαινομενικά έρχεται σε αντίθεση με την παράταση του PT/aPTT, υποδεικνύοντας έτσι την ύπαρξη κάποιου αντιρροπιστικού μηχανισμού. Τα ευρήματα αυτά δεν περιγράφονται στα κλασσικά συγγράματα Αιματολογίας. Η ανευρεθείσα αρνητική συσχέτιση του INR με τον FVII υποδεικνύει κάποιο πιθανό ρόλο αυτού του παράγοντα στον παθογενετικό μηχανισμό, εύρημα το οποίο χρήζει περαιτέρω διερεύνησης. Η ανεύρεση αυξημένων επιπέδων TFPI υποστηρίζει την υπόθεση της αναστολής του συμπλόκου TF/FVII από τον TFPI και αντιπροσωπεύει έναν πιθανό μηχανισμό παράτασης του PT/INR and aPTT. Αυτή η υπόθεση καθώς και η υπόθεση της κατανάλωσης του FVII μέσω συμπλόκου με τον TF και η ενεργοποίηση του PAR2 υποδοχέα μέσω του συμπλόκου TF/FVII, ο οποίος φαίνεται να υπερεκφράζεται σε διάφορα μοντέλα φλεγμονής, χρήζουν περαιτέρω διερεύνησης. Πρέπει να σημειωθεί, ότι οι διαταραχές της αιμόστασης δε συνοδεύονται από αιμορραγική διάθεση και δε θα πρέπει να αξιολογούνται στην καθ΄ημέραν κλινική πράξη. Επιπλέον μελέτες απαιτούνται ώστε να αποσαφηνιστούν οι υποκείμενοι παθογενετικοί μηχανισμοί και να καθοριστεί η ενδεχόμενη προγνωστική σημασία του φαινομένου.Hodgkin lymphoma (HL) is a relative rare lymphoproliferative disorder. Its unique biology is attributed to the fact that the characteristic Hodgkin-Reed-Sternberg cells constitute only 1% of the lymphoma mass, while the remainder is composed by lymphocytes, eosinophils, granulocytes, macrophages, which form the tumor microenvironment. The microenvironment differs among the histologic subtypes of HL and plays a crucial role in the pathogenesis of the disease. An inflammatory picture associated to advanced stages and B- symptoms is characteristic of the disease. Elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, haptoglobins, ferritin, α2- and γ globulins, white blood cell and platelet count and decreased hemoglobin and albumin levels are frequently observed as manifestations of this inflammatory syndrome. Considering our clinical observation that HL patients frequently present at diagnosis with high-normal or prolonged prothrombin time (PT) / INR, which is not an established knowledge as described in textbooks, we intended to describe this phenomenon and study possible underlying mechanisms. Hence, we analyzed plasma and serum samples of 35 consecutive, newly diagnosed HL patients diagnosed between 2/2018 and 2/2019 in our Centre, before treatment initiation. We observed that 29% of these patients presented with prolonged PT/INR (>1.2) and 37% activated partial thromboplastin time (aPTT) (>40 sec), which was more pronounced in advanced disease stages and in patients with B-symptoms. Additionally, D-Dimers were found to be elevated (>0.5 μg/ml) in 58% of patients and correlated with high IPS (≥3). Aiming to study underlying pathogenetic mechanisms, we measured plasma activity of factors II, V, VII, X along with serum levels of TFPI. A negative correlation between PT and FVII was shown, while no relevant correlation with TFPI was observed. Moreover, elevated serum TFPI levels were detected in 66% of the patients, albeit not associated with disease clinical and laboratory characteristics. Additionally, elevated activity of FII, FV and FX was noted, which was correlated with laboratory parameters of the inflammatory syndrome. In conclusion, our data suggest that prolonged PT/INR and aPTT are collateral findings related to disease activity and raised due to excessive activation of hemostasis in the setting of the disease-associated inflammatory syndrome in HL. Similarly, the elevation of FII, FV and FX is interpreted within the context of the same inflammatory syndrome, which is seemingly in contrast with the prolonged PT/aPTT, suggesting an underlying compensatory mechanism. These findings have not yet been described in Hematology textbooks. The negative correlation of INR with FVII implies a possible role in the pathogenetic mechanism, that needs to be further studied. The hypothesis of inactivation of TF/FVII complex from TFPI is supported by the elevated TFPI serum levels and may imply a potential role in prolonged PT/INR and aPTT. The hypothesis of consumption of FVII in a complex with TF and the activation of PAR2 receptor via TF/FVII, which seems to be overexpressed in inflammation, needs to be further evaluated. Of note, coagulation disorders in HL patients are not accompanied by bleeding tendencya and should not be taken into consideration in clinical practice. Additional studies are warranted, in order to clarify the underlying pathogenetic mechanisms and determine their potential prognostic significance

Immunotherapy in Hodgkin Lymphoma: Present Status and Future Strategies

Although classical Hodgkin lymphoma (cHL) is usually curable, 20–30% of the patients experience treatment failure and most of them are typically treated with salvage chemotherapy and autologous stem cell transplantation (autoSCT). However, 45–55% of that subset further relapse or progress despite intensive treatment. At the advanced stage of the disease course, recently developed immunotherapeutic approaches have provided very promising results with prolonged remissions or disease stabilization in many patients. Brentuximab vedotin (BV) has been approved for patients with relapsed/refractory cHL (rr-cHL) who have failed autoSCT, as a consolidation after autoSCT in high-risk patients, as well as for patients who are ineligible for autoSCT or multiagent chemotherapy who have failed ≥ two treatment lines. However, except of the consolidation setting, 90–95% of the patients will progress and require further treatment. In this clinical setting, immune checkpoint inhibitors (CPIs) have produced impressive results. Both nivolumab and pembrolizumab have been approved for rr-cHL after autoSCT and BV failure, while pembrolizumab has also been licensed for transplant ineligible patients after BV failure. Other CPIs, sintilimab and tislelizumab, have been successfully tested in China, albeit in less heavily pretreated populations. Recent data suggest that the efficacy of CPIs may be augmented by hypomethylating agents, such as decitabine. As a result of their success in heavily pretreated disease, BV and CPIs are moving to earlier lines of treatment. BV was recently licensed by the FDA for the first-line treatment of stage III/IV Hodgkin lymphoma (HL) in combination with AVD (only stage IV according to the European Medicines Agency (EMA)). CPIs are currently being evaluated in combination with AVD in phase II trials of first-line treatment. The impact of BV and CPIs was also investigated in the setting of second-line salvage therapy. Finally, combinations of targeted therapies are under evaluation. Based on these exciting results, it appears reasonable to predict that an improvement in survival and a potential increase in the cure rates of cHL will soon become evident

Very Early Onset of Therapy-Related Acute Myeloid Leukemia with 11q23 Rearrangement Presenting with Unusual PET Findings after R-DA-EPOCH for Primary Mediastinal Large B-Cell Lymphoma

Background: R-DA-EPOCH is an effective regimen for PMLBCL, which permits the omission of consolidative radiotherapy in the majority of patients. Patient: We describe a 27-year-old female patient, who achieved a complete remission after treatment with six cycles of R-DA-EPOCH (up to the final level). At 6 months after the end of treatment, PET/CT revealed an unexpected, diffusely increased (18)FDG uptake by the bone marrow. Simultaneously, pancytopenia with monocytosis was observed. Result: The patient was diagnosed with therapy-related myelodysplastic syndrome, which rapidly evolved into acute myeloid leukemia (t-MDS/AML) with MLL rearrangements. She achieved a complete remission after induction therapy, received an allogenic transplant and remains disease-free 2 years later. Conclusions: The extremely early onset of t-MDS/AML, together with the unexpected PET/CT findings make this case unique and highlights the need for the accurate estimation of the possible dose-dependent risk of t-MDS/AML after R-DA-EPOCH in the real-life setting in patients with PMLBCL

Very Early Onset of Therapy-Related Acute Myeloid Leukemia with 11q23 Rearrangement Presenting with Unusual PET Findings after R-DA-EPOCH for Primary Mediastinal Large B-Cell Lymphoma

Background: R-DA-EPOCH is an effective regimen for PMLBCL, which permits the omission of consolidative radiotherapy in the majority of patients. Patient: We describe a 27-year-old female patient, who achieved a complete remission after treatment with six cycles of R-DA-EPOCH (up to the final level). At 6 months after the end of treatment, PET/CT revealed an unexpected, diffusely increased 18FDG uptake by the bone marrow. Simultaneously, pancytopenia with monocytosis was observed. Result: The patient was diagnosed with therapy-related myelodysplastic syndrome, which rapidly evolved into acute myeloid leukemia (t-MDS/AML) with MLL rearrangements. She achieved a complete remission after induction therapy, received an allogenic transplant and remains disease-free 2 years later. Conclusions: The extremely early onset of t-MDS/AML, together with the unexpected PET/CT findings make this case unique and highlights the need for the accurate estimation of the possible dose-dependent risk of t-MDS/AML after R-DA-EPOCH in the real-life setting in patients with PMLBCL

Serum ferritin levels in previously untreated classical Hodgkin lymphoma: correlations and prognostic significance

Serum ferritin (SF) is frequently elevated in classical Hodgkin lymphoma (cHL). We report on its prognostic significance in an unselected series of 529 cHL patients treated with state-of-the-art therapy. Higher baseline levels correlated with markers of advanced/aggressive disease. SF levels were significantly higher in male and older patients, those with high body mass index and mixed cellularity histology. The strongest correlation was recorded between SF and complement reactive protein (CRP) levels. Gender-specific SF cutoffs which provided the best discrimination in terms of freedom from progression (FFP) were identified. In multivariate analysis elevated SF levels, advanced stage and high lactate dehydrogenase (LDH) were independent prognostic factors of inferior FFP. SF also appears to retain independent prognostic significance for progression-free survival (PFS) but not for overall survival (OS). In conclusion, SF levels in cHL reflect disease activity and are associated with adverse patient outcomes