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Background. The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)—related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. Methods. A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. Results. One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extra-lymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0–1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. Conclusions. More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I–IV and 26.6% for grades II–IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.

The clinical presentation of chronic myeloid leukemia (CML) at diagnosis differs in children compared to adults. At younger age, anemia appears to be frequent at diagnosis, but its prevalence and its impact on prognosis are not well known. In the International Registry of Childhood CML, we selected children and adolescents in chronic phase at diagnosis of CML and treated upfront with imatinib. We examined their hemoglobin level at diagnosis according to the WHO grades to assess the prevalence of anemia and its impact on response to tyrosine kinase inhibitors (TKIs). Data on 430 patients were included. Anemia at diagnosis was observed in 350 patients (81%), with a mean hemoglobin level of 96.4 g/l (SD 23.6). Among them, 182 patients (52%) presented with moderate anemia and 110 (31%) with severe anemia while 58 (17%) had mild anemia. Compared with mild and no anemia, moderate and severe forms were significantly associated with younger age at diagnosis, asthenia, splenomegaly, and increased leukocyte and basophil counts. Delays in achieving major and deep molecular responses were significantly increased for patients with moderate and severe anemia, and also failure of imatinib treatment was more frequent in these two sub-cohorts. However, hemoglobin level was not significantly associated with survival. Anemia at diagnosis of pediatric CML was frequent and may be considered as a prognostic factor.

DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature. Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy. Two-month-old girl with delayed development, T-B-NK+ SCID, and macrocytic anemia presented features of Omenn syndrome. Whole exome sequencing revealed two novel, heterozygous variants (c.2312 G>A, p.Arg771Gly and c.776+5G>T, p.Pro260*) in the LIG1 gene (NM_000234.1). Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol. Mixed donor-recipient chimerism was observed, with 60-70% chimerism in the mononucleated cell compartment and over 90% in T-lymphocyte compartment, but autologous myeloid recovery. Stable CD4+ and CD8+ T-cell counts above 200/µL were achieved after 2 months, but the patient remained transfusion-dependent. Despite satisfactory immunological reconstitution, the second transplantation due to constitutional hemolytic defect has been considered. In light of possible re-transplantation, an issue of optimal conditioning protocol with sufficient myeloid engraftment is important. For the first time Omenn syndrome is described in a compound heterozygote carrying two the novel variants p.Arg771Gly and p.Pro260* in the LIG1 gene. Patients diagnosed with SCID and Omenn syndrome showing macrocytic anemia, should be screened for DNA ligase I deficiency.

Gadolinium based contrast agents (GBCAs) are widely used in magnetic resonance imaging, but recently, high signal intensity in the cerebellum structures was reported after repeated administrations of contrast- enhanced magnetic resonance images. The aim of this systematic review was to investigate the association between increased signal intensity in the dentate nucleus and globus pallidus in the brain and repeated administrations of GBCAs. Additionally, we focused on possible short- and long-term consequences of gadolinium use in those patients. Systematic review of retrospective investigations in PubMed and Medline was performed in July 2016. Primary outcomes included the presence of increased signal intensity within the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in patients following administrations of GBCAs. Two independent reviewers were responsible for search and data extraction. 25 publications satisfied inclusion criteria (19 magnetic resonance images analyses, 3 case reports; 3 autopsy studies). Magnetic resonance images of 1247 patients with increased signal intensity on unenhanced T1-weighted MR images were analyzed as well as tissue specimens from 27 patients. Signal intensity correlated positively with the exposure to GBCAs and was greater after serial administrations of linear nonionic than cyclic contrast agents. Gadolinium was detected in all tissue examinations. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance images were associated with previous administration of GBCAs. Signal intensity correlated negatively with stability of contrast agents. Clinical significance of gadolinium deposition in the brain remains unclear. There is a strong need for further research to identify type of gadolinium deposited in the brain as well as to gather knowledge about long-term consequences.

Gemtuzumab ozogamicin (GO), one of the first targeted drugs used in oncology, consists of an anti-cluster of differentiation 33 (CD33) monoclonal antibody bound to a derivative of cytotoxic calicheamicin. After the drug withdrawn in 2010 due to a significantly higher rate of early deaths, GO regained approval in 2017 for the treatment of newly diagnosed, refractory, or relapsed acute myeloid leukemia (AML) in adults and children over 15 years of age. The objective of the study was a retrospective analysis of clinical characteristics, treatment outcomes, and GO toxicity profile in children with primary refractory or relapsed (R/R) AML treated in Poland from 2008 to 2022. Data were collected through the Polish Registry of Acute Myeloid Leukemia. From January 2008 to December 2022, 35 children with R/R AML were treated with GO in seven centers of the Polish Pediatric Leukemia and Lymphoma Study Group. Most of the children (30 of 35) received only one GO cycle in combination with various chemotherapy cycles (IDA-FLA, DOXO-FLA, FLA, FLAG, and others). Eighteen children (51%) achieved complete remission (CR), 14 did not respond to treatment, and three progressed. GO therapy was followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 18 children in CR. The 5-year overall survival (OS) after GO therapy was 37.1% ± 8.7% for the total cohort. There was a trend toward a superior outcome in patients with strong expression of CD33 expression (over 50% positive cells) compared with that in patients with lower expression of CD33 (OS, 41.2% ± 11.9% versus 27.8% ± 13.2%; p = 0.5; 5-year event-free survival, 35.4% ± 11.6% versus 25.7% ± 12.3%; p = 0.5, respectively). Children under 15 years have better outcome (OS, 34.9% ± 10.4% versus 30% ± 14.5%, p = 0.3). The most common adverse events were bone marrow aplasia, fever of unknown origin, infections, and elevated liver enzyme elevation. Sinusoidal obstruction syndrome occurred in two children. The use of GO in severely pretreated children, including those under 15 years of age, with previous failure of AML treatment is a feasible and effective bridging therapy to allo-HSCT with an acceptable toxicity profile.

Venetoclax, the best established BH3-mimetic, is a practice-changing proapoptotic drug in blood cancers in adults. In paediatrics the data are fewer but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the in-terventions could be potentially molecularly guided as vulnerabilities to BH3-mimetics were re-ported. Currently venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated so far with venetoclax in Poland. We set out to gather this experience to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data as available in November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with hematologic complete remission (CR), was reported in 5 patients out of ten, whereas 5 patient did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe BH3-mimetics have clinical activity in children and should be available to pae-diatric haemato-oncology practitioners in well-selected applications.

Despite the great advancements in treatment strategies for hematological malignancies (HMs) over the years, their effective treatment remains challenging. Conventional treatment strategies are burdened with several serious drawbacks limiting their effectiveness and safety. Improved understanding of tumor immunobiology has provided novel anti-cancer strategies targeting selected immune response components. Currently, immunotherapy is counted as the fourth pillar of oncological treatment (together with surgery, chemo- and radiotherapy) and is becoming standard in the treatment regimen, alone or in combination therapy. Several categories of immunotherapies have been developed and are currently being assessed in clinical trials for the treatment of blood cancers, including immune checkpoint inhibitors, antigen-targeted antibodies, antibody–drug conjugates, tumor vaccines, and adoptive cell therapies. However, monoclonal antibodies (mAbs) and their derivatives have achieved the most notable clinical outcome so far. Since the approval of rituximab for treating B-cell malignancies, the availability of mAbs against tumor-specific surface molecules for clinical use has flourished. Antibody-based therapy has become one of the most successful strategies for immunotherapeutic cancer treatment in the last few decades, and many mAbs have already been introduced into standard treatment protocols for some hematologic malignancies. To further increase the efficacy of mAbs, they can be conjugated to radioisotopes or cytostatic drugs, so-called antibody–drug conjugates. Moreover, with the growing recognition of T-cell immunity’s role in cancer development, strategies aimed at enhancing T cell activation and inhibiting mechanisms that suppress T cell function are actively being developed. This review provides a comprehensive overview of the current status of immunotherapeutic strategies based on monoclonal antibodies and their derivatives, including antibody–drug conjugates, bispecific T-cell engagers, and checkpoint inhibitors, approved for the treatment of various HMs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are prone to developing acute kidney injury (AKI). Markers of kidney damage: kidney injury molecule (KIM)-1, interleukin (IL)-18, and neutrophil gelatinase-associated lipocalin (NGAL) may ease early diagnosis of AKI. The aim of this study was to assess serum concentrations of KIM-1, IL-18, and NGAL in children undergoing HSCT in relation to classical markers of kidney function (creatinine, cystatin C, estimated glomerular filtration rate (eGFR)) and to analyze their usefulness as predictors of kidney damage with the use of artificial intelligence tools. Serum concentrations of KIM-1, IL-18, NGAL, and cystatin C were assessed by ELISA in 27 children undergoing HSCT before transplantation and up to 4 weeks after the procedure. The data was used to build a Random Forest Classifier (RFC) model of renal injury prediction. The RFC model established on the basis of 3 input variables, KIM-1, IL-18, and NGAL concentrations in the serum of children before HSCT, was able to effectively assess the rate of patients with hyperfiltration, a surrogate marker of kidney injury 4 weeks after the procedure. With the use of the RFC model, serum KIM-1, IL-18, and NGAL may serve as markers of incipient renal dysfunction in children after HSCT.