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In this single-center analysis, we evaluated the trends in 5185 hematopoietic cell transplantations performed between 1990 and 2022. The study group comprised 3237 allogeneic (alloHCT) and 1948 autologous (autoHCT) hematopoietic cell transplantations. In the multivariate analysis, there was an improvement in event-free-survival (EFS) after autoHCT (HR 0.6, 95% CI 0.4-0.7, p < 0.0001) due to reduced cumulative incidence of relapse in the last five years (56% in 2010-2014 vs. 38% in 2015-2022). An improvement in EFS after alloHCT over time was observed (HR 0.33, 95% CI 0.23-0.48, p < 0.0001), which was due to reduced non-relapse mortality. No difference in cumulative relapse incidence was observed over the last decade for allografted patients. Survival after autoHCT improved in Hodgkin's disease (HR 0.1, 95% CI 0.1-0.3), multiple myeloma (HR 0.4, 95% CI 0.2-0.7) and solid tumors (HR 0.2, 95% CI 0.2-0.4), while after alloHCT, improvement was observed in acute myeloid leukemia (HR 0.3, 95% CI 0.1-0.5), acute lymphoblastic leukemia (HR 0.2, 95% CI 0.1-0.5), Hodgkin's disease (HR 0.1, 95% CI 0.0-0.4), non-Hodgkin's lymphomas and chronic lymphocytic leukemia (HR 0.2, 95% CI 0.0-0.6), inborn diseases (HR 0.2, 95% CI 0.2-0.4) and acquired aplastic anemia with matched related donors and matched unrelated donors (HR 0.3, 95% CI 0.2-0.8).

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., (© 2021. The Author(s).)

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.

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., (© 2020 S. Karger AG, Basel.)

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)., Competing Interests: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Monoclonal gammopathy of renal significance (MGRS) is a new nosology in modern nephrology and oncohematology. MGRS is defined as kidney injury due to nephrotoxic monoclonal immunoglobulin produced by the B-cell line clone which does not reach the hematological criteria for specific treatment initiation. Monoclonal proteins pathological effects on kidney parenchyma result in irreversible decline of kidney function till the end stage renal disease that in line with the position of International Consensus of hematologists and nephrologists determinates critical necessity for clone specific treatment in patients with MGRS despite the absence of hematological indications for treatment initiation. Main challenge of MGRS in Russian Federation is an inaccessibility of an in-time diagnostic and appropriate treatment for the great majority of patients due to the following reasons: 1) limited knowledge about the MGRS among hematologists and nephrologists; 2) lack of necessary diagnostic resources in most health-care facilities; 3) lack of approved clinical recommendations and medical economic standards for treatment of this pathological entity. Consensus document comprises the opinion of experts leading nephrologists and hematologists of Russian Federation on the problem of MGRS including the incoherence in nosology classification, diagnostics approach and rationale for clone specific treatment. Consensus document is based on conclusions and agreements reached during the conference of leading nephrologists and hematologists of Russia which was held in the framework of symposia Plasma cell dyscrasias and lymphoproliferative diseases: modern approaches to therapy, 1516 of March 2019, Pavlov First Saint Petersburg State Medical University. The present Consensus is intended to define the principal practical steps to resolve the problem of MGRS in Russian Federation that are summarized as final clauses.

Acute and chronic steroid-refractory graft-versus-host disease (srGVHD) is a life-threatening complication of allogeneic stem cell transplantation. There are a number of reports on case series describing efficacy of ruxolitinib in both acute and chronic srGVHD. We conducted a prospective study (NCT02997280) in 75 patients with srGVHD (32 acute, 43 chronic, 41 adults, and 34 children). Patients with chronic GVHD had severe disease in 83% of cases, and acute GVHD patients had grade III-IV disease in 66% of cases. The overall response rate (ORR) was 75% (95% CI 57-89%) in acute GVHD and 81% (95% CI 67-92%) in chronic. Overall survival was 59% (95% CI 49-74%) in acute group and 85% (95% CI 70-93%). The major risk factors for lower survival were grade III-IV gastrointestinal involvement (29% vs 93%, p = 0.0001) in acute form and high disease risk score in chronic (65% vs 90%, p = 0.038). Toxicity was predominantly hematologic with 79% and 44% of grade III-IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR (p = 0.31, p = 0.35), survival (p = 0.44, p = 0.12) and toxicity (p > 0.93). The study demonstrated that ruxolitinib is an effective option in acute and chronic srGVHD and can be used both in adults and children.

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 2 ) 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)., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

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.

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.

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., (Copyright © 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

An important area in modern malignant tumor therapy is the optimization of antitumor drugs pharmacokinetics. The use of some antitumor drugs is limited in clinical practice due to their high toxicity. Therefore, the strategy for optimizing the drug pharmacokinetics focuses on the generation of high local concentrations of these drugs in the tumor area with minimal systemic and tissue-specific toxicity. This can be achieved by encapsulation of highly toxic antitumor drug (vincristine (VCR) that is 20-50 times more toxic than widely used the antitumor drug doxorubicin) into nano- and microcarriers with their further association into therapeutically relevant cells that possess the ability to migrate to sites of tumor. Here, we fundamentally examine the effect of drug carrier size on the behavior of human mesenchymal stem cells (hMSCs), including internalization efficiency, cytotoxicity, cell movement, to optimize the conditions for the development of carrier-hMSCs drug delivery platform. Using the malignant tumors derived from patients, we evaluated the capability of hMSCs associated with VCR-loaded carriers to target tumors using a three-dimensional spheroid model in collagen gel. Compared to free VCR, the developed hMSC-based drug delivery platform showed enhanced antitumor activity regarding those tumors that express CXCL12 (stromal cell-derived factor-1 (SDF-1)) gene, inducing directed migration of hMSCs via CXCL12 (SDF-1)/CXCR4 pathway. These results show that the combination of encapsulated antitumor drugs and hMSCs, which possess the properties of active migration into tumors, is therapeutically beneficial and demonstrated high efficiency and low systematic toxicity, revealing novel strategies for chemotherapy in the future.

Outcome data were collected from the European Society for Blood and Marrow Transplantation registry on 373 children from 120 centers with relapsed leukemia (214 with acute lymphoblastic leukemia [ALL] and 159 with acute myelogenous leukemia [AML]) who underwent second allogeneic hematopoietic stem cell transplantation (HSCT) between 2004 and 2013. Overall survival (OS) was 38% at 2 years and 29% at 5 years, and leukemia-free survival (LFS) was 30% at 2 years and 25% at 5 years. Median follow-up after second HSCT was 36.4 months in the ALL group and 50.2 months in the AML group. In the ALL group, OS was 43% at 2 years and 33% at 5 years, and LFS was 34% at 2 years and 31% at 5 years. In the AML group, OS was 32% at 2 years and 24% at 5 years, and LFS was 24% at 2 years and 17% at 5 years. The 2-year nonrelapse mortality (NRM) rate was 22% in the ALL group and 18% in the AML group. Favorable prognostic factors (P < .05) for OS and LFS included >12 months between transplantations and chronic graft-versus-host disease after the first HSCT (in both groups), complete response before the second HSCT (ALL group only), and age >12 years (AML group only). Findings were more consistent over time in the ALL group, with no significant differences between 2-year and 5-year rates of relapse, NRM, and LFS. Children with relapsed acute leukemias have a substantial likelihood of long-term survival following second HSCT. Given the many novel targeted and immunomodulation therapies currently under development, it is important to identify specific patient subpopulations that may benefit from a second HSCT compared with those better suited to new approaches., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs)., Methods: We retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph+ ALL in molecular remission, treated between 2007 and 2014., Results: In univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P = 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P = 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P = 0.69), while overall survival rates were 70%, 70% and 69% (P = 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio [HR], 1.5, P = 0.12) and URD-HSCT (HR, 1.6, P = 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)-based regimens was associated with reduced risk of relapse (HR, 0.65, P = 0.02) and overall mortality (HR, 0.67, P = 0.01)., Conclusion: In the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph+ ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph+ ALL., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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)., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

CRISPR-Cas9 is a revolutionary genome-editing technology that has enormous potential for the treatment of genetic diseases. However, the lack of efficient and safe, non-viral delivery systems has hindered its clinical application. Here, we report on the application of polymeric and hybrid microcarriers, made of degradable polymers such as polypeptides and polysaccharides and modified by silica shell, for delivery of all CRISPR-Cas9 components. We found that these microcarriers mediate more efficient transfection than a commercially available liposome-based transfection reagent (>70% vs. <50% for mRNA, >40% vs. 20% for plasmid DNA). For proof-of-concept, we delivered CRISPR-Cas9 components using our capsules to dTomato-expressing HEK293T cells-a model, in which loss of red fluorescence indicates successful gene editing. Notably, transfection of indicator cells translated in high-level dTomato knockout in approx. 70% of transfected cells. In conclusion, we have provided proof-of-principle that our micro-sized containers represent promising non-viral platforms for efficient and safe gene editing., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Large number of studies was published about predictive value of cytokines for graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Recently, there has been a growing interest in GVHD prophylaxis with post-transplant cyclophosphamide (PTCy). Clinical data on the dynamics of proinflammatory cytokines with this prophylaxis is lacking. In this study, we have measured the levels of IL-17, IL-6, IL-8, IFN-γ and TNF-α in plasma on days -7, 0, +7, +14 and after engraftment in 20 patients with acute GVHD and 40 matched control patients with PTCy-based prophylaxis. Low levels of IL-8 (p=0.04) on day +7 and IFN-γ (p=0.03) after engraftment were associated with grade II-IV acute GVHD. The same pattern was observed for severe acute GVHD. Low IFN-γ after engraftment was also associated with increased non-relapse mortality (p=0.014). No impact of cytokine levels on overall survival and relapse incidence was observed (p>0.05). In conclusion, the dynamics of IL-8 and IFN-γ in GVHD patients after PTCy was different from previously reported after conventional prophylaxis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Stem cell engineering-the manipulation and functionalization of stem cells involving genetic modification-can significantly expand their applicability for cell therapy in humans. Toward this aim, reliable, standardized, and cost-effective methods for cell manipulation are required. Here we explore the potential of magnetic multilayer capsules to serve as a universal platform for nonviral gene transfer, stem cell magnetization, and magnetic cell separation to improve gene transfer efficiency. In particular, the following experiments were performed: (i) a study of the process of internalization of magnetic capsules into stem cells, including capsule co-localization with established markers of endo-lysosomal pathway; (ii) characterization and quantification of capsule uptake with confocal microscopy, electron microscopy, and flow cytometry; (iii) intracellular delivery of messenger RNA and separation of gene-modified cells by magnetic cell sorting (MACS); and (iv) analysis of the influence of capsules on cell proliferation potential. Importantly, based on the internalization of magnetic capsules, transfected cells became susceptible to external magnetic fields, which made it easy to enrich gene-modified cells using MACS (purity ∼95%), and also to influence their migration behavior. In summary, our results underline the high potential of magnetic capsules in stem cell functionalization, namely (i) to increase gene-transfer efficiency and (ii) to facilitate enrichment and targeting of transfected cells. Finally, we did not observe a negative impact of the capsules used on the proliferative capacity of stem cells, proving their high biocompatibility.

The only proven cure for Shwachman-Diamond syndrome (SDS) bone marrow failure is allogeneic hematopoietic stem cell transplantation (HSCT). However HSCT with donors other than HLA-identical siblings is associated with high mortality and unfavorable prognosis. This paper presents the first experience of HSCT treatment of SDS using an unaffected HLA-identical sibling produced through preimplantation genetic diagnosis (PGD). The patient was a 6-year-old blood transfusion-dependent SDS baby girl with secondary myelodysplastic syndrome, for whom no HLA-identical donor was available. As a result of PGD, two unaffected HLA matched embryos were identified; one of them was randomly selected for transfer, resulting in a clinical pregnancy and birth of an apparently healthy child. The patient underwent allogeneic transplantation of cord blood hematopoietic stem cells, together with bone marrow from this sibling, resulting in complete hemopoietic recovery. The patient was no longer transfusion-dependent and had normal blood values 160 days after transplantation.

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.

Background: Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after ≥2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). To the authors' knowledge, there currently are no data regarding factors influencing transplantation outcomes., Methods: The authors retrospectively studied outcomes of transplantation for cases of PREF ALL reported to European Society for Blood and Marrow Transplantation registry. Eligibility criteria for the current analysis included adult patients who underwent their first HCT for PREF ALL between 2000 and 2012. PREF disease was defined as the failure to achieve a morphological CR after ≥2 courses of induction chemotherapy., Results: Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively., Conclusions: Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL. Cancer 2017;123:1965-1970. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

The implementation of RNAi technology into the clinical practice has been significantly postponing due to the issues regarding to the delivery of naked siRNA predominantly to target cells. Here we report the approach to enhance the efficiency of siRNA delivery by encapsulating the siRNA into new carrier systems which are obtained via the combination of widely used layer-by-layer technique and in situ modification by sol-gel chemistry. We used three types of siRNAs (NP-717, NP-1155 and NP-1496) in encapsulated form as new therapeutic agents against H1N1 influenza virus infection. By employing the hybrid microcontainers for the siRNA encapsulation we demonstrate the reduction of viral nucleoprotein (NP) level and inhibition of influenza virus production in infected cell lines (MDCK and A549). The obtained hybrid carriers based on assembled biodegradable polyelectrolytes and sol-gel coating possess several advantages such as a high cell uptake efficiency, low toxicity, efficient intracellular delivery of siRNAs and the protection of siRNAs from premature degradation before reaching the target cells. These findings underpin a great potential of versatile microencapsulation technology for the development of anti-viral RNAi delivery systems against influenza virus infection.

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., (© 2017 S. Karger GmbH, Freiburg.)

We designed novel hybrid inorganic/organic capsules with unique physicochemical features enabling multimodal triggering by physical (UV light, ultrasound) and chemical (enzymatic treatment) stimuli. Notably, the UV- and ultrasound response was achieved by a synergetic combination of TiO 2 and SiO 2 nanostructures which were in situ deposited into the polymer shell of microcapsules during sol-gel synthesis. This results in the formation of a composite hybrid shell with enhanced mechanical stability. Such sol-gel modification reduces the permeability of the capsule shell to allow for small molecule encapsulation. At the same time, these hybrid capsules consist of degradable polypeptides and polysaccharides and can be decomposed in response to enzymatic reaction. Upon employing different modes of treatment (UV-light, ultrasound or enzymatic degradation) we can stimulate different mechanisms of cargo release at desired times. Importantly, such capsules have been shown to be non-cytotoxic and can be internalized into human mesenchymal stem cells (MSCs) and cervical cancer cell lines (HeLa) revealing intracellular degradation. This work demonstrates that our hybrid capsules possess a triple stimuli-responsive effect, which is of capital importance for the future design and application of multimodal responsive platforms to improve externally stimulated release of bioactive compounds and their healthcare performance.

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., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this report, we investigated intracellular redox induced drug release in cancerous cells and human mesenchymal stem cells (MSCs) as an example of healthy cells using redox-responsive microcapsules with covalently bonded anti-cancer drug (doxorubicin) via the amine-reactive cross-linker, 3,3'-dithiobis(sulfosuccinimidyl propionate) containing disulfide bond. Such rationally designed capsules with incorporated redox-sensitive cross-linker are capable of controllable Dox release in the presence of glutathione (GSH) due to a thiol-cleavable disulfide bonds. The treatment of human MSCs and human cervical cancer cell line (HeLa) with Dox-conjugated capsules showed that the Dox release was observed only when capsules incubated with HeLa cells which can be induced by high GSH level in cancerous (HeLa) cells. Moreover, the results of cell viability indicated that Dox-conjugated capsules are more effective when inducing cell death of HeLa than free Dox improving the anti-tumor efficacy of chemotherapeutic drug and simultaneously they possess lower cytotoxicity against MSCs compared to cancerous cells. Such properties are important in design of smart drug carriers for efficient cancer therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has significantly increased survival rate and quality of life for patients with CML. Despite the high efficacy of imatinib, not all patients benefit from this treatment. Resistance to imatinib can develop from a number of mechanisms. One of the main reasons for treatment failure is a mutation in the BCR-ABL gene, which leads to therapy resistance and clonal evolution. Clearly, new treatment approaches are required for patients who are resistant to imatinib. However, mutated clones are usually susceptible to second-generation TKIs, such as nilotinib and dasatinib. The choice of the therapy depends on the type of mutation. A large trial program showed that dasatinib is effective in patients previously exposed to imatinib. However, for a minority of patients who experience treatment failure with TKI or progress to advanced-phase disease, allogeneic stem cell transplantation (allo-SCT) remains the therapeutic option. In spite of the high curative potential of allo-SCT, its high relapse rate still requires a feasible strategy of posttransplant treatment and prophylaxis. We report a case of a CML patient with primary resistance to first-line TKI therapy. The patient developed an undifferentiated blast crisis. Before dasatinib therapy, the patient was found to have an F317L mutation. He was successfully treated with dasatinib followed by allo-SCT. In the posttransplant period, preemptive dasatinib treatment was used to prevent disease relapse.

Aim: To study the incidence and risk factors of bacterial infections and the efficiency of empirical antibacterial therapy in patients in the early period after allogeneic hematopoietic stem cell transplantation (allo-HSCT)., Subjects and Methods: The study included 155 patients who had undergone allo-HSCT. Myeloablative conditioning was used in 39% of the patients. All the patients with neutropenia (NP) received antibiotic prophylaxis with fluoroquinolones until recovery of white blood cell counts or before systemic antibiotic therapy. Antibiotic therapy and a change of antibiotics were considered effective in achieving persistent apyrexia and positive clinical changes., Results: The incidence of febrile neutropenia (FNP) in the patients after allo-HSCT was 63%. The duration of grade 4 leukopenia did not depend on the conditioning regimen. Neutropenic fever was noted in 68% of the patients with NP lasting longer 10 days. In shorter-duration NP, the rate of fever was 52%. Among the patients with mucositis, the frequency of FNP episodes was significantly higher (69% versus 52%; p=0.02). The diverse spectrum of isolated bacteria was represented as gram-positive cocci in 45% of cases; Klebsiella pneumoniae and Enterobacter cloacae were more common among gram-negative ones (24%). The efficiency of empirical antibiotic therapy was 57% (25% for monotherapy, 53% for combined treatment regimens); the early mortality was 2%., Conclusion: Infection-related FNP is noted in 68% of the patients in the early posttransplantation period and the risk factors of its development are NP duration, oral colonization with pathogens, and the absence of invasive mycosis after allo-HSCT. Antibacterial prophylaxis significantly decreases the incidence of bacterial complications. Empirical monotherapy with third- or fourth-generation cephalosporins and carbapenems against infections in a transplantation patient is as effective as their combination with aminoglycosides.

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., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Reduced-intensity conditioning regimens have been used extensively in adults with hematologic malignancies. To address whether this is a feasible approach for children with acute lymphoblastic leukemia, we evaluated transplant outcomes in 38 recipients transplanted from 1995-2005 for whom this was their first transplant. The median age at transplant was 12 years, and 47% had performance scores <90%. Disease status was first complete remission (CR) in 13%, > or =CR2 in 60% of patients, and 22% had active disease at transplantation. Matched related donors were available for a third of patients, about half of whom received bone marrow (BM) and the others, peripheral blood progenitor cells. Sixty percent of unrelated donor transplant recipients received peripheral blood progenitor cells. The day-100 probability of grade II-IV acute graft-versus-host disease was 37% and the 3-year probability of chronic graft-versus-host disease, 26%. At 3 years, the probability of treatment-related mortality was 40%, relapse 37%, and disease-free survival 30%. These data indicate long-term DFS can be achieved using reduced-intensity conditioning regimens in children with acute lymphoblastic leukemia. Given the relatively small cohort, these findings must be validated in a larger population., (Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

In this report, we describe two patients with idiopathic hypereosinophilic syndrome (HES) who received a non-myeloablative allogeneic transplantation following a reduced-intensity preparative regimen of melphalan and fludarabine. In both cases, complete donor chimaerism and remission were achieved, and have lasted for more than 10 months. This report provides proof of principle for the feasibility of non-myeloablative transplantation for patients with idiopathic HES, who can show co-morbidity due to eosinophilic infiltration of their organs.