Blinatumomab as postremission therapy replaces consolidation and substantial parts of maintenance chemotherapy and results in stable MRD negativity in children with newly diagnosed B-lineage ALL.

The bispecific T cell-binding antibody blinatumomab (CD19/CD3) is widely and successfully used for the treatment of children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here, we report the efficacy of a single course of blinatumomab instead of consolidation chemotherapy to eliminate minimal residual disease (MRD) and maintain stable MRD-negativity in children with primary BCP-ALL.Between February 2020 and November 2022, 177 children with non-high-risk BCP-ALL were enrolled in the ALL-MB 2019 pilot study (NCT04723342). Patients received the usual risk-adapted induction therapy according to the ALL-MB 2015 protocol. Those who achieved a complete remission at the end of induction (EOI) received treatment with blinatumomab immediately after induction at a dose of 5 µg/m2/day for 7 days and 21 days at a dose of 15 µg/m2/day, followed by 12 months of maintenance therapy. MRD was measured using multicolor flow cytometry (MFC) at the EOI, then immediately after blinatumomab treatment, and then four times during maintenance therapy at 3-month intervals.All 177 patients successfully completed induction therapy and achieved a complete hematological remission. In 174 of these, MFC-MRD was measured at the EOI. 143 patients (82.2%) were MFC-MRD negative and the remaining 31 patients had varying degrees of MFC-MRD positivity.MFC-MRD was assessed in all 176 patients who completed the blinatumomab course. With one exception, all patients achieved MFC-MRD negativity after blinatumomab, regardless of the MFC-MRD score at EOI. One adolescent girl with high MFC-MRD positivity at EOI remained MFC-MRD positive. Of 175 patients who had completed 6 months of maintenance therapy, MFC-MRD data were available for 156 children. Of these, 155 (99.4%) were MFC-MRD negative. Only one boy with t(12;21) (p13;q22)/ETV6::RUNX1 became MFC-MRD positive again. The remaining 174 children had completed the entire therapy. MFC-MRD was examined in 154 of them, and 153 were MFC-MRD negative. A girl with hypodiploid BCP-ALL showed a reappearance of MFC-MRD with subsequent relapse.In summary, a single 28-day course of blinatumomab immediately after induction, followed by 12 months of maintenance therapy, is highly effective in achieving MRD-negativity in children with newly diagnosed non-high risk BCP-ALL and maintaining MRD-negative remission at least during the treatment period.

Novel and Promising Strategies for Therapy of Post-Transplant Chronic GVHD.

Despite the achievements that have increased viability after the transplantation of allogeneic hematopoietic stem cells (aHSCT), chronic graft-versus-host disease (cGVHD) remains the main cause of late complications and post-transplant deaths. At the moment, therapy alternatives demonstrate limited effectiveness in steroid-refractory illness; in addition, we have no reliable data on the mechanism of this condition. The lack of drugs of choice for the treatment of GVHD underscores the significance of the design of new therapies. Improved understanding of the mechanism of chronic GVHD has secured new therapy goals, and organized diagnostic recommendations and the development of medical tests have ensured a general language and routes for studies in this field. These factors, combined with the rapid development of pharmacology, have helped speed up the search of medicines and medical studies regarding chronic GVHD. At present, we can hope for success in curing this formidable complication. This review summarizes the latest clinical developments in new treatments for chronic GVHD.

Antiviral Cell Products against COVID-19: Learning Lessons from Previous Research in Anti-Infective Cell-Based Agents.

COVID-19 is a real challenge for the protective immunity. Some people do not respond to vaccination by acquiring an appropriate immunological memory. The risk groups for this particular infection such as the elderly and people with compromised immunity (cancer patients, pregnant women, etc.) have the most serious problems in developing an adequate immune response. Therefore, dendritic cell (DC) vaccines that are loaded ex vivo with SARS-CoV-2 antigens in the optimal conditions are promising for immunization. Lymphocyte effector cells with chimeric antigen receptor (CAR lymphocytes) are currently used mainly as anti-tumor treatment. Before 2020, few studies on the antiviral CAR lymphocytes were reported, but since the outbreak of SARS-CoV-2 the number of such studies has increased. The basis for CARs against SARS-CoV-2 were several virus-specific neutralizing monoclonal antibodies. We propose a similar, but basically novel and more universal approach. The extracellular domain of the immunoglobulin G receptors will be used as the CAR receptor domain. The specificity of the CAR will be determined by the antibodies, which it has bound. Therefore, such CAR lymphocytes are highly universal and have functional activity against any infectious agents that have protective antibodies binding to a foreign surface antigen on the infected cells.

Chondroitin Sulfate and Fucosylated Chondroitin Sulfate as Stimulators of Hematopoiesis in Cyclophosphamide-Induced Mice.

The immunosuppression and inhibition of hematopoiesis are considered to be reasons for the development of complications after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation. Chondroitin sulfate (CS), isolated from the fish Salmo salar, and fucosylated chondroitin sulfate (FCS), isolated from the sea cucumber Apostichopus japonicus, were studied for their roles as stimulators of hematopoiesis in a model of cyclophosphamide-induced immunosuppression in mice. The recombinant protein r G-CSF was applied as a reference. The studied polysaccharides were shown to stimulate the release of white and red blood cells, as well as platelets from bone marrow in immunosuppressed mice, while r G-CSF was only responsible for the significant increase in the level of leucocytes. The analysis of different populations of leucocytes in blood indicated that r G-CSF mainly stimulated the production of neutrophils, whereas in the cases of the studied saccharides, increases in the levels of monocytes, lymphocytes and neutrophils were observed. The normalization of the level of the pro-inflammatory cytokine IL-6 in the serum and the recovery of cell populations in the spleen were observed in immunosuppressed mice following treatment with the polysaccharides. An increase in the proliferative activity of hematopoietic cells CD34(+)CD45(+) was observed following ex vivo polysaccharide exposure. Further study on related oligosaccharides regarding their potential as promising drugs in the complex prophylaxis and therapy of hematopoiesis inhibition after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation seems to be warranted.

Potential Use of Mesenchymal Multipotent Cells for Hemopoietic Stem Cell Transplantation: Pro and Contra.

The potential of mesenchymal multipotent (stem) cells (MSC) to modify immune reactions and mediate hematopoiesis boosted great interest for their use in allogeneic hemopoietic stem cell transplantation. Because of MSC production of a wide range of cytokines and growth factors, these cells are included in the therapy of graft-versus-host disease (GVHD). A number of clinical studies have demonstrated safety and efficacy of MSC-based therapy in acute GVHD. Japan and some other countries approved biomedical cell products on the base of allogeneic bone marrow (BM) MSCs as medical agents for acute GVHD treatment. Besides, MSCs may form BM stroma and improve hematopoiesis. Simultaneous transplantation of hematopoietic stem cells and MSCs effectively improved engraftment and prevented GVHD in transplantation of umbilical cord blood and human leukocyte antigens-incompatible BM stem cells. The review presents the analysis of clinical studies of MSCs in allogeneic hematopoietic stem cell transplantation and discusses different approaches for improvement of MSC-based GVHD treatment and prophylaxis.

Immune Pathogenesis of COVID-19 Intoxication: Storm or Silence?

Dysregulation of the immune system undoubtedly plays an important and, perhaps, determining role in the COVID-19 pathogenesis. While the main treatment of the COVID-19 intoxication is focused on neutralizing the excessive inflammatory response, it is worth considering an equally significant problem of the immunosuppressive conditions including immuno-paralysis, which lead to the secondary infection. Therefore, choosing a treatment strategy for the immune-mediated complications of coronavirus infection, one has to pass between Scylla and Charybdis, so that, in the fight against the "cytokine storm," it is vital not to miss the point of the immune silence that turns into immuno-paralysis.

Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are exceptionally rare neoplasms, which are often driven by rearranged tyrosine kinases. METHODS: This study considered 33 consecutive patients with IMT (median age, 6.6; age range, 0.6-15.8 years). RNA and cDNA were successfully obtained in 29 cases. The molecular analysis included sequential tests for 5'/3'-end unbalanced gene expression, variant-specific PCR, and next-generation sequencing (NGS). RESULTS: 5'/3'-end unbalanced ALK expression was revealed in 15/29 (52%) IMTs. Strikingly, all these tumors demonstrated high amount of ALK protein detected by immunohistochemistry. Variant-specific PCR was capable of identifying the type of ALK rearrangement in 11/15 IMTs with 5'/3'-end unbalanced ALK expression. The remaining four tumors were analyzed by NGS; two known and two novel (CLTC-ins6del84-ALK and EEF1G-ALK) ALK rearrangements were detected. Five IMTs demonstrated 5'/3'-end unbalanced ROS1 expression, and all these tumors carried TFG-ROS1 fusion. Nine tumors, which were negative for 5'/3'-end unbalanced ALK/ROS1 expression, were subjected to further analysis. Variant-specific PCR revealed two additional tumors with gene rearrangements (TFG-ROS1 and ETV6-NTRK3). The remaining seven IMTs were tested by NGS; single instances of TFG-ROS1 and novel SRF-PDGFRb translocations were detected. CONCLUSIONS: Twenty-four of 29 IMTs (83%) were shown to have druggable rearrangements involving tyrosine kinases, 20 of these 24 gene fusions were detectable by simple and inexpensive PCR assay, which is based on the detection 5'/3'-end unbalanced gene expression.

PPP3CB contributes to poor prognosis through activating nuclear factor of activated T-cells signaling in neuroblastoma.

We previously identified a gain-of-function mutation in PPP3CB in a neuroblastoma (NB) with MYCN amplification. Here we investigated the functional and clinical role of PPP3CB in NB. High PPP3CB expression was an independent indicator predicting poor prognosis of NB. Overexpression of wildtype or mutated PPP3CB (PPP3CBmut) promoted cell growth, but PPP3CB knockdown decreased cell growth in NB cells. Forced expressions of PPP3CB and PPP3CBmut activated NFAT2 and NFAT4 transcription factors and inhibited GSK3ß activity, resulting in the increase in the expressions of c-Myc, MYCN, and ß-catenin, which were downregulated in response to PPP3CB knockdown. Treatment with calcineurin inhibitor cyclosporin A (CsA) or FK506 suppressed cell proliferation and induced apoptotic cell death in both MYCN-amplified and MYCN-non-amplified NB cell lines. Expression of PPP3CB protein was decreased in response to two calcineurin inhibitors. c-Myc, MYCN, and ß-catenin were downregulated at the mRNA and protein levels in CsA or FK506-treated NB cells. Our data indicate that elevated expression of PPP3CB and the expression of its constitutively active mutant contribute to the aggressive behavior of NB tumors and therefore suggest that inhibition of calcineurin activity might have therapeutic potential for high-risk NB.

Malignant rhabdoid tumor of the liver presented with initial tumor rupture.

Malignant rhabdoid tumor (MRT) of the liver is a rare, highly aggressive tumor of early childhood. We report a 6-month-old boy who was diagnosed with MRT of the liver and presented with spontaneous tumor rupture. The patient underwent intensified chemotherapy and a radical surgical procedure. Twenty four months from the time of the diagnosis, he is alive without evidence of disease. This is the second report of prolonged survival after initial rupture of hepatic MRT.

Childhood leukemia and lymphoma: time trends and factors affecting survival in five Southern and Eastern European Cancer Registries.

PURPOSE: Within Europe, incidence and mortality rates of childhood leukemia and lymphoma are rather heterogeneous. The present study comprising data from five Southern and Eastern European Cancer Registries aims to compare time trends and examine whether sociodemographic variables, clinical parameters, and proxies of efficient care affect survival. METHODS: Data spanning 1996-2010 were obtained for a total of 3,041 newly diagnosed childhood leukemia and 1,183 lymphoma cases reported by the Greek Nationwide Registry for Childhood Hematological Malignancies, Bulgarian National Cancer Registry, Moscow Region and Turkey (Antalya and Izmir) Cancer Registries. Poisson modeling for the evaluation of time trends and multivariate Cox regression analysis for the assessment of prognostic factors were performed. RESULTS: The incidence of leukemia was increasing in all cases, with Bulgaria and Greece presenting statistically significant annual changes (+3.5, and +1.7 %, respectively), followed by marginally increasing trends in Izmir and Moscow; by contrast, there was a remarkable, statistically significant, decreasing mortality trend for leukemia. Rates for lymphoma remained flat. Greece experienced almost twofold better survival rates for both leukemia and lymphoma, probably due to its higher socioeconomic status during the study period. Overall, patients with leukemia living in rural areas had a 28 % lower prognosis (RR: 1.28, 95 % CI 1.03-1.59), pointing to effects of remoteness, when the most privileged country (Greece) was excluded from the analysis. CONCLUSIONS: The favorable mortality trends highlight the progress in Southern-Eastern European countries along their trajectory to converge with Northern-Western EU counterpart states. Socioeconomic status may act as a multipotent factor underlying the study findings.