Publications by authors named "Ivan Moiseev"

24 Publications

  • Page 1 of 1

Extracorporeal Photopheresis in Children with Chronic Graft-Versus-Host Disease.

Pharmaceuticals (Basel) 2021 Aug 17;14(8). Epub 2021 Aug 17.

RM Gorbacheva Research Institute, Pavlov University, 197022 St. Petersburg, Russia.

Chronic graft versus host disease (cGVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It significantly decreases survival and quality of life. The present study demonstrates retrospective data on extracorporeal photopheresis (ECP) in children with cGVHD. A total of 42 children with steroid-refractory cGVHD were enrolled in the study. The majority of patients had acute leukemia ( = 32, 76%). All patients received ECP as second ( = 18, 43%) or third ( = 24, 57%) line of therapy. Initial ECP schedule consisted of bimonthly regimen for two consecutive days with possibility of further tapering according to response. Any concurrent treatment administered before ECP could be continued if considered necessary. Complete response to ECP was registered in seven (17%) patients and partial response in 24 (57%). Overall response according to organ involvement was as follows: skin ( = 24, 75%), mucous membranes ( = 16, 73%), liver ( = 8, 80%), gut ( = 4, 80%), lungs ( = 2, 22%) and joints ( = 2, 67%). Five-year overall, progression-free and failure-free survival was 57%, 56% and 30%, respectively. Non-relapse mortality at 5 years was 14%. We didn't observe any clinically significant complications in children that could be attributed to the procedure. ECP remains important and safe treatment option in children with cGVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph14080808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398239PMC
August 2021

Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML.

Bone Marrow Transplant 2021 Jul 30. Epub 2021 Jul 30.

University Medical Center Hamburg Eppendorf, Department of Stem Cell Transplantation, Hamburg, Germany.

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n = 96) or accelerated phase (n = 51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in ≥CP2 (n = 70), in AP (n = 40) or in BC (n = 37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34 count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors ≤36 years and with higher CD34 dose in the graft.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01410-xDOI Listing
July 2021

Evaluating the Effect of 3'-UTR Variants in and on Their Tissue-Specific Expression by miRNA Target Prediction.

Curr Issues Mol Biol 2021 Jul 6;43(2):605-617. Epub 2021 Jul 6.

Bioinformatics Research Center, Pavlov First Saint Petersburg Medical State University, 197022 St. Petersburg, Russia.

Untranslated gene regions (UTRs) play an important role in controlling gene expression. 3'-UTRs are primarily targeted by microRNA (miRNA) molecules that form complex gene regulatory networks. Cancer genomes are replete with non-coding mutations, many of which are connected to changes in tumor gene expression that accompany the development of cancer and are associated with resistance to therapy. Therefore, variants that occurred in 3'-UTR under cancer progression should be analysed to predict their phenotypic effect on gene expression, e.g., by evaluating their impact on miRNA target sites. Here, we analyze 3'-UTR variants in and genes in the context of myelodysplastic syndrome (MDS) development. The key features of this analysis include an assessment of both "canonical" and "non-canonical" types of mRNA-miRNA binding and tissue-specific profiling of miRNA interactions with wild-type and mutated genes. As a result, we obtained a list of and variants likely altering the miRNA sites and, therefore, potentially leading to the observed tissue-specific gene downregulation. All identified variants have low population frequency consistent with their potential association with pathology progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cimb43020044DOI Listing
July 2021

Graft-versus-Host Disease Prophylaxis with Post-Transplantation Bendamustine in Patients with Refractory Acute Leukemia: A Dose-Ranging Study.

Transplant Cell Ther 2021 07 7;27(7):601.e1-601.e7. Epub 2021 May 7.

RM Gorbacheva Research Institute, Pavlov University, Saint-Petersburg, Russian Federation.

The prognosis of acute leukemia refractory to induction chemotherapy or immunotherapy is dismal. Salvage allogeneic hematopoietic stem cell transplantation (HSCT) is widely used option for these patients, but only 10% to 15% of patients are cured by the procedure. Preclinical studies indicate that substitution of post-transplantation cyclophosphamide with bendamustine (PTB) in a prophylaxis regimen may be associated with an augmented graft-versus-leukemia (GVL) reaction. The aim of this study was to establish the optimal dose of PTB and evaluate the antileukemic effect of HSCT with this type of graft-versus-host disease (GVHD) prophylaxis. In the prospective trial (NCT02799147), PTB was administered in doses of 140, 100, and 70 mg/m on days +3 and +4. Myeloablative conditioning with fludarabine and oral busulfan was provided to all patients. The first 12 patients received single-agent PTB, and subsequent patients received combination therapy with tacrolimus and mycophenolate mofetil (MMF). Inclusion criteria were acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and ≥5% clonal blasts in the bone marrow. The study cohort comprised 22 patients with AML and 5 with ALL. Seven patients were enrolled in the 140 mg/m group (due to a stopping rule), and 10 each were enrolled in the 100 mg/m and 70 mg/m groups. Primary refractory disease was documented in 41% of the patients, and secondary refractory was documented in 59%. The median blast count in the bone marrow at the start of the conditioning was 18% (range, 6% to 97%). Transplantation was performed with a matched sibling donor in 5 patients, a matched or mismatched unrelated donor in 15, and a haploidentical donor in 7. Engraftment was documented in 93% of the patients, including 89% with complete remission and 63% without measurable residual disease. After PTB prophylaxis, we observed an unusual complication, a cytokine release syndrome (CRS), in 70% of the patients, including grade 3 to 5 CRS in 44%. The most frequent clinical symptoms included high fever in 67% of patients, abnormal liver function tests in 67%, pancreatitis in 63%, skin vasculitis in 56%, enterocolitis in 48%, inflammation of oral mucosa in 37%, disseminated intravascular coagulation in 37%, and central nervous system toxicity in 26%. The development of CRS was associated with use of an HLA-mismatched donor (75% versus 20%; P = .0043). Classic acute GVHD was documented in 44% of the patients. Grade II-IV acute GVHD was associated with grade 3 to 5 CRS (67% versus 25%; P = .031). Moderate and severe chronic GVHD in the 100-day survivors were more often observed after single-agent PTB than after the combination immunosuppression (100% versus 18%; P = .002). A relatively low relapse rate was observed for this patient population. Three-year overall survival was 28% (95% confidence interval [CI], 13% to 46%), and event-free survival was 29% (95% CI, 13% to 46%). Nonrelapse mortality was 46% (95% CI, 25% to 64%), and the cumulative incidence of relapse was 26% (95% CI, 11% to 44%). No relapses were documented after day +100. There were no statistically significant differences among the dose groups (P = .3481); however, survival was higher in the 100 mg/kg group. Survival was higher in patients with AML compared with those with ALL (35% versus 0%; P = .0157). PTB represents a promising option to augment the GVL effect in refractory AML; however, the high CRS-associated mortality necessitates additional studies to reduce the risk of this complication. Thus, routine clinical application of PTB cannot be currently recommended. Combination immunosuppression with tacrolimus and MMF partially ameliorates these complications, at least in the setting of HLA-matched allografts. Biological mechanisms of CRS and GVL after PTB require further elucidation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.03.032DOI Listing
July 2021

Presence of viremia during febrile neutropenic episodes in patients undergoing chemotherapy for malignant neoplasms.

Am J Hematol 2021 06 3;96(6):719-726. Epub 2021 May 3.

St.Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

The importance of viral infections as a leading cause of morbidity and mortality is well documented in severely immunosuppressed patients undergoing allogeneic stem cell transplantation. By contrast, viral infections generally receive less attention in patients with malignant disorders undergoing chemotherapy, where the onset of neutropenic fever is mostly associated with bacterial or fungal infections, and screening for viral infections is not routinely performed. To address the occurrence of invasive viral infections in a clinical setting commonly associated with less pronounced immunosuppression, we have prospectively screened 237 febrile neutropenic episodes in pediatric (n = 77) and adult (n = 69) patients undergoing intensive chemotherapy, primarily for treatment of acute leukemia. Serial peripheral blood specimens were tested by RQ-PCR assays for the presence and quantity of the clinically relevant viruses CMV, EBV, HHV6 and HAdV, commonly reactivated in highly immunocompromised patients. Viremia was documented in 36 (15%) episodes investigated, including the detection of HHV6 (n = 14), EBV (n = 15), CMV (n = 6), or HAdV (n = 1). While low or intermediate levels of viremia (<10 virus copies/mL) were commonly associated with bacterial or fungal co-infection, viremia at higher levels (>10 copies/mL) was documented in patients without evidence for other infections, raising the possibility that at least in some instances the onset of fever may have been attributable to the virus detected. The observations suggest that viral infections, potentially resulting from reactivation, might also play a clinically relevant role in patients receiving chemotherapy for treatment of malignant neoplasms, and routine screening for viremia in this clinical setting might be warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26177DOI Listing
June 2021

High mutation burden in the checkpoint and micro-RNA processing genes in myelodysplastic syndrome.

PLoS One 2021 17;16(3):e0248430. Epub 2021 Mar 17.

RM Gorbacheva Research Institute, Pavlov University, Saint-Petersburg, Russian Federation.

A number of sequencing studies identified the prognostic impact of somatic mutations in myelodysplastic syndrome (MDS). However the majority of them focused on methylation regulation, apoptosis and proliferation genes. Despite the number of experimental studies published on the role of micro-RNA processing and checkpoint genes in the development of MDS, the clinical data about mutational landscape in these genes is limited. We performed a pilot study which evaluated mutational burden in these genes and their association with common MDS mutations. High prevalence of mutations was observed in the genes studied: 54% had mutations in DICER1, 46% had mutations in LAG3, 20% in CTLA4, 23% in B7-H3, 17% in DROSHA, 14% in PD-1 and 3% in PD-1L. Cluster analysis that included these mutations along with mutations in ASXL1, DNMT3A, EZH2, IDH1, RUNX1, SF3B1, SRSF2, TET2 and TP53 effectively predicted overall survival in the study group (HR 4.2, 95%CI 1.3-13.6, p = 0.016). The study results create the rational for incorporating micro-RNA processing and checkpoint genes in the sequencing panels for MDS and evaluate their role in the multicenter studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248430PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968630PMC
March 2021

Nivolumab discontinuation and retreatment in patients with relapsed or refractory Hodgkin lymphoma.

Ann Hematol 2021 Mar 2;100(3):691-698. Epub 2021 Feb 2.

RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russian Federation.

Immune checkpoint inhibitors (ICI) have demonstrated high therapeutic efficacy in relapsed or refractory classical Hodgkin lymphoma (r/r cHL). Nevertheless, despite the accumulated data, the question of the ICI therapy duration and efficacy of nivolumab retreatment remains unresolved. In this retrospective study, in a cohort of 23 adult patients with r/r cHL who discontinued nivolumab in complete response (CR), the possibility of durable remission achievement (2-year PFS was 55.1%) was demonstrated. Retreatment with nivolumab has demonstrated efficacy with high overall response rate (ORR) and CR (67% and 33.3% respectively). At the final analysis, all patients were alive with median PFS of 16.5 months. Grade 3-4 adverse events (AEs) were reported in 36% of patients, and there was no deterioration in terms of nivolumab retreatment-associated complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04429-8DOI Listing
March 2021

A Phase 2 Study of Nivolumab Using a Fixed Dose of 40 mg (Nivo40) in Patients With Relapsed/Refractory Hodgkin Lymphoma.

Hemasphere 2020 Oct 23;4(5):e480. Epub 2020 Sep 23.

Raisa Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia.

The introduction of nivolumab has changed the landscape of relapsed/refractory classical Hodgkin lymphoma (r/r cHL) treatment. Despite its clinical importance, this therapy may remain inaccessible for a significant number of patients worldwide, especially in low-income countries, due to its high cost. The results of pharmacokinetic analysis and clinical observations suggest the potential efficacy of low dose nivolumab in r/r cHL patients. The aim of this trial was to assess the efficacy and safety of nivolumab at a fixed dose of 40 mg in patients with r/r cHL. The study included 30 patients with r/r cHL, treated with 40 mg nivolumab every 2 weeks. The median dose of nivolumab per kilogram bodyweight was 0.59 mg/kg (0.4-1 mg/kg). Median follow up was 19.2 months (range 12.7-25.4). The objective response rate was 70%, with 13 (43.3%) patients achieving a complete response. Median PFS was 18.4 months (95% CI, 11.3 to 18.5 months) with 18-month PFS of 53.6% (95% CI, 32%-71%). At the time of analysis, 96.7% of patients were alive with a median OS not reached. Severe (grade 3-5) adverse events were observed in 4 patients (13.3%). Nivolumab in a fixed dose of 40 mg was efficient in patients with r/r cHL, independent from dose per kg bodyweight. The results of this study are in good agreement with previously reported data and create a rationale for further studies aimed to define the optimal dosing regimen of nivolumab for the treatment of r/r cHL. Registered at www.clinicaltrials.gov (NCT03343665).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HS9.0000000000000480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523758PMC
October 2020

Immune checkpoints bone marrow expression as the predictor of clinical outcome in myelodysplastic syndrome.

Leuk Res Rep 2020 28;14:100215. Epub 2020 Jun 28.

R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russian Federation.

Aims: In our single-center retrospective study we evaluated whether level of different checkpoint molecules in bone marrow biopsies at diagnosis affect the clinical course of patients with myelodysplastic syndrome (MDS).

Methods And Results: A consecutive cohort of 55 MDS patients treated in our center from 2003 to 2018 with available bone marrow biopsies at time of diagnosis was studied. We used a technique able to detect the expression of the following antigens: PD-1, PD-L1, PD-L2, LAG-3, Gal-9, TIM-3, CD80. The association between expression level and 3-year overall and relapse-free survival and time-to-progression was analyzed. Intensive expression of TIM-3 was observed in 100% of cases. Also, in most cases, moderate Gal-9 expression was observed. With 3-year follow-up disease progression was seen in 72.9% of patients with high CD80 level and 52.1% of patients with low CD80 level (p=0.04). PD-1, CTLA4 and TIM-3 ligands were co-expressed in the majority of patients. General checkpoint ligand expression level also was associated with increased 3-year incidence of progression: 67.2% of patients with high level of checkpoint ligands progressed, while in the group with low checkpoint ligand expression level progression was observed only in 33.3% of cases (p=0.059). There was an association between the expression of checkpoint molecules CD80, PD-L2, TIM3, the number of bone marrow blasts and risk according to IPSS and IPSS-R scales.

Conclusions: Our preliminary study underlined heterogeneous immune checkpoint molecules expression in MDS and warrants further studies to define the role of this heterogeneity and develop optimal treatment approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lrr.2020.100215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364161PMC
June 2020

A Study of Safety and Efficacy of Nivolumab and Bendamustine (NB) in Patients With Relapsed/Refractory Hodgkin Lymphoma After Nivolumab Monotherapy Failure.

Hemasphere 2020 Jun 8;4(3):e401. Epub 2020 Jun 8.

Raisa Gorbacheva Memorial Institute of Children Oncology Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russian Federation.

This single-center prospective clinical trial evaluated the combination of nivolumab plus bendamustine (NB) as a salvage regimen in classical Hodgkin lymphoma patients after failure of nivolumab monotherapy. A total of 30 patients received nivolumab (3 mg/kg) on D1,14 and bendamustine (90 mg/m) on D1, 2 of a 28-day cycle for up to 3 cycles. The ORR was 87% with 57% CR, 30% PR. With median follow-up of 25 months, the estimated 2-year OS was 96,7% (95% CI, 90.2%-100%), PFS was 23,3% (95% CI, 8.2%-38.4%) median PFS was 10.2 months (95% CI, 7.7-14.2 months) with median DOR 6.6 months (95% CI 3.9-11.6 months). Ten patients (33.3%) experienced grade 3 to 4 AE during therapy. Infections were most common AEs of the combined therapy. NB was a highly efficient salvage regimen in relapsed/refractory cHL with a manageable toxicity profile and modest potential for achievement of long-term remission. Registered at www.clinicaltrials.gov (#NCT0334365).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HS9.0000000000000401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306298PMC
June 2020

Timing of Post-Transplantation Cyclophosphamide Administration in Haploidentical Transplantation: A Comparative Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2020 10 6;26(10):1915-1922. Epub 2020 Jul 6.

Hematology Department, Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, Paris, France; Sorbonne Universités, INSERM, Centre de Recherche Saint-Antoine, UPMC Univ Paris 06, Paris, France; European Society for Blood and Marrow Transplantation, Paris, France.

The timing of immunosuppressive therapy used in combination with post-transplantation cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (haplo-HSCT) is not standardized. We evaluated the schedules of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on days +3 and +4 along with tacrolimus (group 1; n = 215), with cyclosporine A (CSA) and mycophenolate mofetil (MMF) from day +5 (group 2; n = 170), or CSA + MMF from day 0 or 1 with PTCY on days +3 and +5 (group 3; n = 124). Compared with the other 2 groups, patients in group 3 were younger (median age, 46 years; P = .02) and more often received bone marrow (77%; P < .01) and a regimen containing thiotepa, fludarabine, and busulfan (84%; P< .01). At 2 years, overall survival was 44% was in group 1, 48% in group 2, and 59% in group 3 (P= .15); leukemia-free survival (LFS) was 43%, 46%, and 53% (P= .05); and refined graft-versus-host disease-free, relapse-free survival (rGRFS) was 33%, 39%, and 36% (P = .02). The incidence of grade II-IV acute GVHD was 25% in group 1, 39% in group 2, and 18% in group 3 (P< .01); incidence of chronic GVHD was 25%, 21%, and 24% (P= .50); relapse incidence was 36%, 37%, and 26% (P= .02); and nonrelapse mortality was 26%, 20%, and 21% (P= .35). On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCY was associated with a better LFS (hazard ratio [HR], .58; P= .02) and improved rGRFS (HR, .62; P = .02). In this study, the timing of immunosuppression influenced the outcomes of haplo-HSCT with PTCY. An early start of CSA + MMF with PTCY administered on days +3 and +5 improves LFS and rGRFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.06.026DOI Listing
October 2020

A Prospective Pilot Study of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis.

Acta Haematol 2021 23;144(2):158-165. Epub 2020 Apr 23.

R.M. Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint-Petersburg, Russian Federation.

Introduction: This prospective study evaluated a calcineurin inhibitor-free graft-versus-host disease (GVHD) prophylaxis regimen of ruxolitinib in combination with post-transplant cyclophosphamide (PTCy). Patents and Methods: Twenty patients with primary or secondary myelofibrosis were prospectively enrolled. Reduced intensity conditioning was performed, followed by allogeneic stem cell transplantation from related (n = 7) or unrelated (n = 13) donors. GVHD prophylaxis included only PTCy and ruxolitinib (45 mg) from day-7 to day-2, and 15 mg from day+5 to day+100. This trial was registered at www.clinicaltrials.gov as #NCT02806375.

Results: Primary engraftment was documented in 17 patients. One patient experienced primary graft failure and 2 died before engraftment. Eleven patients demonstrated severe poor graft function (SPGF), which required ruxolitinib dose reduction. The regimen was well tolerated, with grade 3-4 non-haematological toxicity in 30%, viral reactivation in 45%, and severe sepsis in 15% of patients. The incidence of acute GVHD grade II-IV was 25%, grade III-IV GVHD was 15%, and moderate chronic GVHD was 20%, with no severe cases. Only 2 patients required systemic steroids. Haematological relapse was documented in 1 patient. Two-year non-relapse mortality was 15%, 2-year overall survival was 85%, and 2-year event-free survival was 72%.

Conclusion: GVHD prophylaxis with PTCy and ruxolitinib is associated with low toxicity, good acute and chronic GVHD control, and low relapse incidence. However, the relatively high rate of SPGF should be taken into account. SPGF could possibly be mitigated by ruxolitinib dose reduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000506758DOI Listing
April 2021

Long-term impact of fecal transplantation in healthy volunteers.

BMC Microbiol 2019 12 30;19(1):312. Epub 2019 Dec 30.

R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation.

Background: Fecal microbiota transplantation (FMT) has been recently approved by FDA for the treatment of refractory recurrent clostridial colitis (rCDI). Success of FTM in treatment of rCDI led to a number of studies investigating the effectiveness of its application in the other gastrointestinal diseases. However, in the majority of studies the effects of FMT were evaluated on the patients with initially altered microbiota. The aim of our study was to estimate effects of FMT on the gut microbiota composition in healthy volunteers and to monitor its long-term outcomes.

Results: We have performed a combined analysis of three healthy volunteers before and after capsule FMT by evaluating their general condition, adverse clinical effects, changes of basic laboratory parameters, and several immune markers. Intestinal microbiota samples were evaluated by 16S rRNA gene and shotgun sequencing. The data analysis demonstrated profound shift towards the donor microbiota taxonomic composition in all volunteers. Following FMT, all the volunteers exhibited gut colonization with donor gut bacteria and persistence of this effect for almost ∼1 year of observation. Transient changes of immune parameters were consistent with suppression of T-cell cytotoxicity. FMT was well tolerated with mild gastrointestinal adverse events, however, one volunteer developed a systemic inflammatory response syndrome.

Conclusions: The FMT leads to significant long-term changes of the gut microbiota in healthy volunteers with the shift towards donor microbiota composition and represents a relatively safe procedure to the recipients without long-term adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12866-019-1689-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938016PMC
December 2019

High prevalence of CD3, NK, and NKT cells in the graft predicts adverse outcome after matched-related and unrelated transplantations with post transplantation cyclophosphamide.

Bone Marrow Transplant 2020 03 20;55(3):544-552. Epub 2019 Sep 20.

R.M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, State Medical University named I.P. Pavlov, Saint-Petersburg, Russian Federation.

The predictive value of graft composition and plasma biomarkers on the outcome of allogeneic HSCT is well known for conventional GVHD prophylaxis based on calcineurin inhibitors with or without antithymocyte globulin. Currently, there is limited data whether these results could be translated to post transplantation cyclophosphamide (PTCy). The prospective extension cohort of NCT02294552 trial enrolled 79 adult patients with acute leukemia in CR. Twenty-six received matched-related bone marrow (BM) grafts with single-agent PTCy and 53 received unrelated peripheral blood stem cell graft (PBSC) with PTCy, tacrolimus, and MMF. The grafts were studied by the flow cytometry, and plasma samples were analyzed by ELISA. In the cluster and major component analysis, we determined that transplantation from donors with high content of CD3, NKT, and CD16-CD56 + subpopulations in the PBSC grafts was associated with poor immunological recovery and compromised event-free survival (50% vs. 80%, HR 2.93, p = 0.015) both due to increased relapse incidence and non-relapse mortality. The significant independent predictor of moderate and severe chronic GVHD was the high prevalence of and iNKT, Vβ11, and double-positive cells in the PBSC grafts from young donors (HR 2.75, p = 0.0483). No patterns could be identified for BM grafts and for plasma biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-019-0665-3DOI Listing
March 2020

Splenectomy following JAK1/JAK2 inhibitor therapy in patients with myelofibrosis undergoing allogeneic stem cell transplantation.

Hematol Oncol Stem Cell Ther 2019 Sep 6;12(3):140-145. Epub 2019 Apr 6.

Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Department of Hematology, Transfusiology, Transplantation, Faculty of Postgraduate Education, Pavlov First Saint Petersburg State Medical University, Saint-Petersburg, Russia.

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only treatment option with curative potential in patients with myelofibrosis (MF). The aim of our study was to evaluate the safety of splenectomy before alloHSCT in MF patients who failed to achieve significant spleen response after ruxolitinib therapy.

Methods: Splenectomy was performed in 12 patients for alloHSCT with myelofibrosis-primary (6 patients), post-polycythemia vera (3 patients). or postessential thrombocythemia (3 patients) between 2016 and 2018. The patients were prospectively included in the study if persistence of splenomegaly ≥ 25 cm was documented after at least 3 months of ruxolitinib therapy. In eight patients subsequent alloHSCT was performed.

Results: Median length of hospital stay was 11 (8-30) days, median follow-up after splenectomy was 20.0 (0.6-31.1) months. No deaths were documented, perioperative morbidity was 50%. Three patients experienced portal vein thrombosis and one experienced splenic vein thrombosis. One patient developed pancreonecrosis and subdiaphragmatic abscess. Mean leukocyte count was significantly higher 1 month after splenectomy than before, 10.7 ± 1.7 versus 6.9 ± 2.3 × 109/L (p = 0.03). Platelets rate significantly elevated starting Day + 7 after splenectomy (p = 0.01). Median time between splenectomy and alloHSCT was 2.6 (0.17-4.5) months. All patients achieved engraftment. In early posttransplant period no cases of severe sepsis, intraabdominal infections were documented. One patient died after alloHSCT due to thrombotic microangiopathy. Seven patients are alive in disease complete remission. No relapses after alloHSCT were observed. Two-year overall survival in the whole group is 90% (95%CI 98-43%).

Conclusion: Splenectomy before alloHSCT might be a promising option in patients who failed to achieve significant spleen response after ruxolitinib therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hemonc.2019.03.001DOI Listing
September 2019

Nivolumab for the treatment of relapsed and refractory classical Hodgkin lymphoma after ASCT and in ASCT-naïve patients.

Leuk Lymphoma 2019 09 4;60(9):2316-2319. Epub 2019 Feb 4.

Raisa Gorbacheva Memorial Institute of Children Oncology Hematology and Transplantation, First Saint Petersburg State Pavlov Medical University , Saint Petersburg , Russian Federation.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2019.1573368DOI Listing
September 2019

Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT.

Bone Marrow Transplant 2019 07 25;54(7):1022-1028. Epub 2018 Oct 25.

Department of Hematology, Military Institute of Medicine, Warsaw, Poland.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated clinical and morphological practices of TA-TMA diagnosis in EBMT centers. Two questionnaires, one for transplant physician and one for morphologist, and also a set of electronic blood slides from 10 patients with TA-TMA and 10 control patients with various erythrocyte abnormalities, were implemented for evaluation. Seventeen EBMT centers participated in the study. Regarding criteria used for TA-TMA diagnosis, centers reported as follows: 41% of centers used the International Working Group (IWG) criteria, 41% used "overall TA-TMA" criteria and 18% used physician's decision. The threshold of schistocytes to establish TA-TMA diagnosis in the participating centers was significantly associated with morphological results of test cases evaluations (p = 0.002). The mean number of schistocytes reported from blood slide analyses were 4.3 ± 4.5% for TA-TMA cases (range 0-19.6%, coefficient of variation (CV) 0.7) and 1.3 ± 1.6% for control cases (range 0-8.3%, CV 0.8). Half of the centers reported schistocyte levels below 4% for 7/10 TA-TMA cases. The intracenter variability was low, indicating differences in the institutional practices of morphological evaluation. In conclusion, the survey identified the need for the standardization of TA-TMA morphological diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-018-0374-3DOI Listing
July 2019

Risk-adapted GVHD prophylaxis with post-transplantation cyclophosphamide in adults after related, unrelated, and haploidentical transplantations.

Eur J Haematol 2018 May 1;100(5):395-402. Epub 2018 Mar 1.

R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russian Federation.

Introduction: Although a number of studies were published on the efficacy of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis, no large studies prospectively evaluated this strategy in related, unrelated, and haploidentical grafts.

Methods: In this study, GVHD prophylaxis for 57 matched bone marrow (MBM) grafts consisted of single-agent PTCy, for 88 matched PBSC grafts (MPBSC) consisted of PTCy, tacrolimus, and mycophenolate mofetil (MMF) 30 mg/kg, and for 55 mismatched grafts (MMGs) consisted of PTCy, tacrolimus and MMF 45 mg/kg.

Results: The study met the primary endpoint to demonstrate equivalent rates of acute GVHD grade II-IV (11%, 17%,19%, P = .46), III-IV (7%, 2%, 6%, P = .41), and moderate and severe chronic GVHD (22%, 11%, 15%, P = .23). There was also no differences in non-relapse mortality (11% vs 15% vs 17%, P = .75), overall survival (63% vs 71% vs 56%, P = .72), event-free-survival (51% vs 66% vs 48%, P = .32) for MBM, MPBSC, and MMG groups, respectively. Toxicity was comparable between groups except higher incidence of nephrotoxicity in combination arms (P = .0005) and higher incidence of graft failures in MMG group (P = .004).

Conclusion: The suggested risk-adapted PTCy-based prophylaxis is feasible and is associated with low GVHD incidence and mortality in all types of grafts. The study was registered on clinicaltrials.gov (NCT02294552).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13030DOI Listing
May 2018

Clinical Correlates and Prognostic Significance of IL-8, sIL-2R, and Immunoglobulin-Free Light Chain Levels in Patients with Myelofibrosis.

Oncol Res Treat 2017 21;40(10):574-578. Epub 2017 Sep 21.

R.M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, State Medical University named I.P. Pavlov, Saint-Petersburg, Russian Federation.

Background: Chronic myeloproliferative neoplasms are characterized by clonal hematopoiesis and persistent inflammatory reaction. In this study, the clinical significance and prognostic impact of several inflammatory markers were evaluated in patients with BCR/ABL-negative myeloproliferative malignancies.

Methods: Serum levels of interleukin-8 (IL-8) and lymphoid-associated activation markers - soluble interleukin-2 receptor (sIL-2R) and immunoglobulin-free light chains (FLC) - were evaluated in patients with primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and compared with the levels in healthy donors.

Results: In 57 MF patients, sIL-2R excess correlated with transfusion-dependent anemia (p = 0.03) and splenomegaly (p = 0.02). There were no statistically significant correlations between sIL-2R and IL-8 levels, but the plasma concentration of κ-FLC positively correlated with the IL-8 level (p = 0.027). In univariate analysis, increased levels of IL-8 (p = 0.016) and sIL-2R (p = 0.010) significantly reduced 1-year overall survival. Only elevated sIL-2R rate retained significance (p = 0.02) in multivariate analysis when Dynamic International Prognostic Scoring System plus (DIPSSplus) risk stratification was added.

Conclusion: We observed an association between FLC and proinflammatory cytokine hyperexpression. Serum cytokine levels and FLC might be a promising approach to predicting and monitoring treatment response in MF patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000477253DOI Listing
October 2018

Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis.

Ann Hematol 2017 Jun 25;96(6):935-942. Epub 2017 Mar 25.

R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia.

A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36-2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II-IV acute GVHD (HR 0.73, 95%CI 0.48-1.10, p = 0.13), but grade III-IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28-0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19-0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-017-2975-0DOI Listing
June 2017

Mesenchymal Stem Cell Magnetization: Magnetic Multilayer Microcapsule Uptake, Toxicity, Impact on Functional Properties, and Perspectives for Magnetic Delivery.

Adv Healthc Mater 2016 12 18;5(24):3182-3190. Epub 2016 Nov 18.

Department of Hematology, Transfusion, and Transplantation, First I. P. Pavlov State Medical University of St. Petersburg, Lev Tolstoy str., 6/8, 197022, Saint Petersburg, Russian Federation.

Mesenchymal stem cells (MSCs) are widely used in cell therapy due to their convenience, multiline differentiation potential, reproducible protocols, and biological properties. The potential of MSCs to impregnate magnetic microcapsules and their possible influence on cell function and ability to response to magnetic field have been explored. Interestingly, the cells suspended in media show much higher ability in internalization of microcapsules, then MSCs adhere into the surface. There is no significant effect of microcapsules on cell toxicity compared with other cell line-capsule internalization reported in literature. Due to internalization of magnetic capsules by the cells, such cell engineering platform is responsive to external magnetic field, which allows to manipulate MSC migration. Magnetically sorted MSCs are capable to differentiation as confirmed by their conversion to adipogenic and osteogenic cells using standard protocols. There is a minor effect of capsule internalization on cell adhesion, though MSCs are still able to form spheroid made by dozen of thousand MSCs. This work demonstrates the potential of use of microcapsule impregnated MSCs to carry internalized micron-sized vesicles and being navigated with external magnetic signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.201600843DOI Listing
December 2016

Graft-versus-Host Disease Prophylaxis in Unrelated Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil.

Biol Blood Marrow Transplant 2016 Jun 10;22(6):1037-1042. Epub 2016 Mar 10.

R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, The First Saint-Petersburg State Medical University named I.P. Pavlov, Saint-Petersburg, Russian Federation.

Clinical efficacy of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has been demonstrated in haploidentical and HLA-matched bone marrow but not in unrelated peripheral blood stem cell (PBSC) transplantations. Also, no direct comparisons have been published with current standard of care, combination of antithymocyte globulin (ATG), calcineurin inhibitors, and either methotrexate or mycophenolate mofetil (MMF). Eighty-six adult patients (median age 34 years; range, 18 to 59) with acute myeloblastic and lymphoblastic leukemia underwent unrelated PBSC transplantation with PTCy, tacrolimus, and MMF as GVHD prophylaxis in the single-center trial (clinicaltrial.govNCT02294552). The control group comprised 125 consecutive historical control patients who received ATG, tacrolimus, and methotrexate or MMF. Cumulative incidences of grades II to IV acute (19% versus 45%, P = .0003), grades III to IV acute (4% versus 27%, P < .0001), and chronic GVHD (16% versus 65%, P < .0001) were significantly lower in the PTCy compared with the ATG group. PTCy-based prophylaxis was associated with reduced incidence of nonrelapse mortality (16% versus 36%, P = .005; HR, .55; 95% CI, .34 to .89) and improved overall survival (69% versus 40%, P = .0007; HR, .43; 95% CI, .26 to .70), event-free survival (65% versus 38%, P = .0006; HR, .49; 95% CI, .31 to .78), and GVHD relapse-free survival (52% versus 12%, P < .0001). PTCy-based prophylaxis also had a better safety profile compared with ATG with reduced incidence of veno-occlusive disease, cytomegalovirus reactivation, invasive mycosis, and reduced severity of mucositis. In this study we demonstrated that PTCy in combination with tacrolimus and MMF is a safe and effective GVHD prophylaxis for unrelated PBSC transplantation. Although there are several limitations of the historical control approach, this study suggests the superiority of a PTCy-based approach over an ATG-based prophylaxis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2016.03.004DOI Listing
June 2016

Level of vascular endothelial growth factor predicts both relapse and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation.

Biol Blood Marrow Transplant 2013 Dec 10;19(12):1677-82. Epub 2013 Sep 10.

R.M. Gorbacheva Memorial Institute of Children's Hematology and Transplantation, I.P. Pavlov State Medical University, 6/8 Lev Tolstoy St, St Petersburg, Russia. Electronic address:

Although the prognostic significance of vascular endothelial growth factor (VEGF) has been researched extensively in patients with hematologic malignancies undergoing chemotherapy, its role in allogeneic hematopoietic stem cell transplantation (HSCT) requires further investigation. The present study evaluated the associations between VEGF level and relapse rate and early complications after HSCT. VEGF levels were analyzed in 91 consecutive patients before the start of conditioning, on day 0, on the day of engraftment, and on the day of diagnosis of veno-occlusive disease (VOD). Compared with a normal level, an elevated high VEGF-A level before conditioning was associated with an increased 2-year relapse rate (55% versus 24%, P = .003; hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.49 to 7.08) and decreased event-free survival (20% versus 44%; P = .022; HR, 2.03; 95% CI, 1.11 to 3.72). No association was found between VEGF level and the incidence of acute GVHD (P > .05). In patients with VOD, VEGF-A level was elevated on day 0 and on the day of VOD diagnosis (P < .05). A low VEGF-A level on day 0 was associated with reduced nonrelapse mortality (14% versus 35%; P = .048; HR, 0.32; 95% CI, 0.10 to 0.99). Our results indicate that a high VEGF-A level before HSCT increases the risk of relapse, and a high level after conditioning is associated with increased risks of early complications and nonrelapse mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2013.08.015DOI Listing
December 2013
-->