Treatment of Acute Promyelocytic Leukemia with High White Cell Blood Counts.

Acute promyelocytic leukemia (APL) with WBC above 10 G/L has long been considered, even in the all-trans retinoic acid (ATRA) era, to carry a relatively poor prognosis (compared to APL with WBC below 10 G/L), due to increased early mortality and relapse. However, early deaths can to a large extent be avoided if specific measures are rapidly instigated, including prompt referral to a specialized center, immediate onset of ATRA and chemotherapy, treatment of coagulopathy with adequate platelet transfusional support, and prevention and management of differentiation syndrome. Strategies to reduce relapse rate include chemotherapy reinforcement with cytarabine and/or arsenic trioxide during consolidation, prolonged maintenance treatment, especially with ATRA and low dose chemotherapy, and possibly, although this is debated, intrathecal prophylaxis to prevent central nervous system relapse. By applying those measures, outcomes of patients with high risk APL have considerably improved, and have become in many studies almost similar to those of standard risk APL patients

Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome

Background The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower‐risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. Objective The aim of this study was to describe the usage and clinical impact of erythropoiesis‐stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. Methods The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. Results ESA treatment (median duration of 27.5 months, range 0–77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65–1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post‐ESA treatment transfusion was 6.1 months (IQR: 4.3–15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0–47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7–3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45–0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39–1.29, P = 0.27). Conclusion Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower‐risk MDS

Autonomous growth potential of leukemia blast cells is associated with poor prognosis in human acute leukemias

We have described a severe combined immunodeficiency (SCID) mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells into a measurable subcutaneous nodule which may be followed by the development of disseminated disease. Utilizing the SCID mouse model, we examined the growth potential of leukemic blasts from 133 patients with acute leukemia, (67 acute lymphoblastic leukemia (ALL) and 66 acute myeloid leukemia (AML)) in the animals after subcutaneous inoculation without conditioning treatment. The blasts displayed three distinct growth patterns: "aggressive", "indolent", or "no tumor growth". Out of 133 leukemias, 45 (33.8%) displayed an aggressive growth pattern, 14 (10.5%) displayed an indolent growth pattern and 74 (55.6%) did not grow in SCID mice. The growth probability of leukemias from relapsed and/or refractory disease was nearly 3 fold higher than that from patients with newly diagnosed disease. Serial observations found that leukemic blasts from the same individual, which did not initiate tumor growth at initial presentation and/or at early relapse, may engraft and grow in the later stages of disease, suggesting that the ability of leukemia cells for engraftment and proliferation was gradually acquired following the process of leukemia progression. Nine autonomous growing leukemia cell lines were established in vitro. These displayed an aggressive proliferation pattern, suggesting a possible correlation between the capacity of human leukemia cells for autonomous proliferation in vitro and an aggressive growth potential in SCID mice. In addition, we demonstrated that patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SClD mice had a poor clinical outcome in patients with ALL as well as AML. Patients whose leukemic blasts grew indolently or whose leukemia cells failed to induce growth had a significantly longer DFS and more favorable clinical course

Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia

A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P &lt; .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P &lt; .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.</p

Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management

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A case-study

Objective: There is an increasing appreciation by clinicans and researchers that psychosocial adjustment and recovery after sustaining traumatic brain injury (TBI) is a multi-factorial process. The aim of the present study was to investigate if premorbid psychosocial functioning and cognitive status post-TBI are linked to long term psychosocial functioning. Methods: 12 patients who had sustained TBI at an average of 14.8 years prior to examination. Psychosocial adjustment both pre-TBI and post-TBI was assessed by using the ASEBA questionnaire, whilst cognitive status was evaluated by administering the Rey Osterreith Complex Figure, Logical Memory I and Logical Memory II, the Hayling and Brixton test, the COWAT verbal fluency test and the NART premorbid intelligence test. Results: Premorbid psychosocial adjustment was found to be linked to post-injury psychosocial functioning. Also, cognitive measures were correlated with aspects of psychosocial functioning. Conclusions: The results from the present study confirm that psychosocial adjustment after TBI is a multifactorial process. It emphasizes the importance of obtaining a history of the inidividual’s premorbid psychosocial and cognitive history. This is a necessity in the context of both clinical practice and research

Chronic myeloid leukemia in children and adolescents: The achilles heel of oncogenesis and tyrosine kinase inhibitors

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. The goal of therapy in children and adolescents is normal life expectancy, without compromising normal growth and development and potential for achievement of milestones in adult life. The perspective of cure is also reflected in the goal of treatment‐free remission, with its surrogate markers, such as deep molecular response, also becoming the new endpoints of therapy efficacy in children and ad-olescents. Chronic myeloid leukemia was a fatal disease to children and adolescents in the past. Following the treatment paradigm of imatinib, it became a chronic disease with the potential of complete remission and even cure without the long‐term hazards of allogeneic hematopoietic cell transplantation. The diagnosis and treatment of CML affect a child’s trajectory through life and important physiological events like development and procreation. © 2021 by the authors. Li-censee MDPI, Basel, Switzerland

Γονιδιακή αστάθεια στα μυελοδυσπλαστικά σύνδρομα χαμηλού κινδύνου.

Εισαγωγή: Τα μυελοδυσπλαστικά σύνδρομα (ΜΔΣ) είναι προϊόν γονιδιακής αστάθειας. Η περιγραφή των μεταλλάξεων και του ανοσολογικού μηχανισμού που τα διέπουν είναι δυνατόν να αποτελέσουν στόχο θεραπείας. Στόχος: Η περιγραφή της γονιδιακής αστάθειας υπό μορφή μεταλλάξεων σε ασθενείς με μυελοδυσπλαστικά σύνδρομα χαμηλού κινδύνου προ και μετά την ανοσοκατασταλτική θεραπεία. Μέθοδοι: Μελετήθηκαν επιλεγμένοι ασθενείς με ΜΔΣ χαμηλού κινδύνου και βαριές κυτταροπενίες. Οι ασθενείς έλαβαν την ίδια ανοσοκατασταλτική θεραπεία με αντιλεμφοκυτταρικό ορό και κυκλοσπορίνη Α. Αναζητήθηκαν σωματικές μεταλλάξεις σε γονίδια που ενέχονται για την παθογένεση των ΜΔΣ με μεθόδους αλληλούχισης νέας γενιάς (NGS). Η ανίχνευση μεταλλάξεων έγινε προ θεραπείας και σε κομβικά σημεία μετά τη θεραπεία, κυρίως κατά την πρόοδο νόσου. Αποτελέσματα: Στην αναδρομική αυτή μελέτη μοναδικού κέντρου συμπεριλήφθηκαν 20 ασθενείς με ΜΔΣ χαμηλού κινδύνου χωρίς del(5q). Οι άσθενείς έλαβαν την ίδια ανοσοκατασταλτική αγωγή. Διαπιστώσαμε ανεξαρτησία από μεταγγίσεις και πλήρη ύφεση σε 45% και 25% των ασθενών αντιστοίχως, με διάμεση διάρκεια απάντησης 68 μήνες. Έντεκα ασθενείς (55%) είχαν υποπλαστικό ΜΔΣ. Ανιχνεύθηκαν 7 μεταλλάξεις -6 σωματικές και μία πιθανώς γαμετική- σε 6 ασθενείς προ της έναρξης της θεραπείας, στα γονίδια ASXL1, U2AF1, ZRSR2 και GATA2. Οι μεταλλάξεις ήταν λιγότερο συχνές στους ασθενείς με υποπλαστικά ΜΔΣ σε σχέση με τους ασθενείς με ΜΔΣ με φυσιολογική ή αυξημένη κυτταροβρίθεια (50% vs. 11%, P=0.03). Δεν διαπιστώθηκε συσχέτιση μεταξύ της παρουσίας μεταλλάξεων και το ποσοστού απάντησης στη θεραπεία ή τη διάρκεια της θεραπείας. Η επιβίωση χωρίς πρόοδο νόσου ήταν μικρότερη στους ασθενείς με προ-θεραπευτικές μεταλλάξεις (διάμεση τιμή 24 μήνες vs. 75 μήνες στους ασθενείς χωρίς μεταλλάξεις, Ρ=0.01). Η αθροιστική επίπτωση ΜΔΣ υψηλού κινδύνου, ΜΔΣ/μυελοϋπερπλαστικών νεοπλασμάτων και οξείας μυελογενούς λευχαιμίας ήταν υψηλότερη στους ασθενείς με μεταλλάξεις (5ετής επίπτωση 33% vs 0 στους ασθενείς χωρίς μεταλλάξεις, Ρ=0.008). Η συνολική επιβίωση ήταν επίσης μικρότερη στους ασθενείς με μεταλλάξεις (διάμεση τιμή 30 μήνες vs. 83 μήνες στους ασθενείς χωρίς μεταλλάξεις, Ρ=0.04). Μόνο ασθενείς με προ-θεραπευτικές μεταλλάξεις σημείωσαν κλωνική εξέλιξη με τη μορφή δευτεροπαθών μεταλλάξεων μετά τη θεραπεία. Μετα-θεραπευτικές μεταλλάξεις ανιχνεύθηκαν στα γονίδια ASXL1, DNMT3A, PHF6, JAK2 V617F, GATA2 Kdel390, IDH1 και ETV6. Αναλύεται η περίπτωση ασθενούς με πιθανώς γαμετικής προέλευσης μετάλλαξη GATA2 και επίκτητες μεταλλάξεις κατά την πρόοδο σε οξεία μυελογενή λευχαιμία στα γονίδια GATA2, DNMT3A, IDH1, ETV6. Συμπέρασμα: Προθεραπευτικές μεταλλάξεις ανιχνεύθηκαν σε 1/3 των ασθενών που επελέγησαν για ανοσοκατασταλτική θεραπεία. Στη μελέτη αυτή, η παρουσία τους μεταλλάξεων δεν αποτελούσε προβλεπτικό παράγοντα της απάντησης στην ανοσοκατασταλτική θεραπεία αλλά συνδεόταν με χειρότερη πρόγνωση.Introduction: Myelodysplastic syndromes (MDS) are the product of genomic instability. Data on somatic mutations in myelodysplastic syndromes within specific therapeutic settings other than hypomethylating agents are scarce. Aim: We aimed at describing genomic instability in lower-risk MDS patients receiving immunosuppressive treatment, by curating somatic mutations detected before and after treatment. Methods: Selected lower-risk MDS patients with severe cytopenias were treated with horse or rabbit antithymocyte globulin with or without ciclosporine A. Somatic mutations in genes involved in the pathogenesis of MDS were detected by next generation sequencing before treatment and at selected time-points after treatment, especially at disease progression. Results: In this monocentric study of 20 patients with non del(5q) lower-risk MDS under immunosuppressive treatment, we observed transfusion independence and complete remission rates of 45% and 25%, respectively. Median response duration was 68 months. Eleven patients (55%) had hypoplastic MDS. We detected 7 mutations -6 somatic, 1 probably germline- in 6 patients before treatment initiation in the following genes: ASXL1, U2AF1, ZRSR2 and GATA2. Mutation frequency was lower in hypoplastic MDS as compared with MDS with normal or increased cellularity (50% vs. 11%, P=0.03). We found no correlation between the presence of mutations and response rate or duration. Progression-free survival (PFS) was lower in patients with pre-treatment mutations (median PFS 24 months vs. 75 months in patients without mutations, Ρ=0.01). Cumulative incidence (CI) of higher-risk MDS, MDS/myeloproliferative neoplasms and acute myeloid leukemia was higher in patients with mutations (5-year CI 33% vs. 0 in patients without mutations, Ρ=0.008). Overall survival (OS) was also lower in patients with mutations (median OS 30 months vs. 83 months in patients without mutations, Ρ=0.04). Post-treatment clonal evolutation with secondary mutations was only documented in patients who carried pre-treatment mutations. Post-treatment mutations included mutations in ASXL1, DNMT3A, PHF6, JAK2 V617F, GATA2 Kdel390, IDH1 and ETV6. We report the case of a patient with probable germline GATA2 mutation and emergence of somatic mutations in GATA2, DNMT3A, IDH1, ETV6 at transformation in acute myeloid leukemia. Conclusion: Pre-treatment mutations were detected in 1/3 of patients selected for immunosuppressive treatment. In this study, detection of mutations was not predictive of response to immunosuppressive treatment but correlated with worse prognosis