Hemopoietic Stem Cell Transplantation Research Articles

Australia and New Zealand Transplant and Cellular Therapies (ANZTCT) position statement: COVID-19 management in patients with haemopoietic stem cell transplant and chimeric antigen receptor T cell.

Patients with post-haemopoietic stem cell transplant or chimeric antigen receptor T -cell (CAR-T) therapy face a significant risk of morbidity and mortality from coronavirus disease 2019 because of their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high-risk population is needed. Whilst we have learned much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to manage our patients optimally.

Lomentospora prolificans Disseminated Infections: A Systematic Review of Reported Cases.

Lomentospora prolificans, a rare, highly virulent filamentous fungus with high rates of intrinsic resistance to antifungals, has been associated with different types of infections in immunocompromised as well as immunocompetent individuals. To systematically address all relevant evidence regarding L. prolificans disseminated infections in the literature. We searched Medline via PubMed and Scopus databases through July 2022. We performed a qualitative synthesis of published articles reporting disseminated infections from L. prolificans in humans. A total of 87 studies describing 142 cases were included in our systematic review. The pathogen was most frequently reported in disseminated infections in Spain (n = 47), Australia (n = 33), the USA (n = 21), and Germany (n = 10). Among 142 reported cases, 48.5% were males. Underlying conditions identified for the majority of patients included malignancy (72.5%), hemopoietic stem cell transplantation (23.2%), solid organ transplantation (16%), and AIDS (2%). Lungs, central nervous system, skin, eyes, heart and bones/joints were the most commonly affected organs. Neutropenia was recorded in 52% of patients. The mortality rate was as high as 87.3%. To the best of our knowledge, this is the first systematic review conducted on disseminated infections due to this rare microorganism. Physicians should be aware that L. prolificans can cause a diversity of infections with high mortality and primarily affects immunocompromised and neutropenic patients.

A Self-Help Manual for Psychological Distress and Quality of Life During a Haemopoietic Stem-Cell Transplant: An Effectiveness and Acceptability Pilot.

Haemopoietic stem-cell transplantation (HSCT) can be a highly distressing procedure that negatively impacts quality of life (QoL). Self-help interventions can help improve psychopathology and wellbeing in patients with physical illness, but have rarely been trialled with HSCT recipients. This study aimed to pilot the utility of a self-help manual intervention during the acute phase of HSCT. Forty autologous and allogeneic HSCT candidates were randomly assigned to a self-help manual intervention or treatment as usual (TAU). Psychological distress (BSI-18) and QoL (FACT-BMT-Vs4) were measured pre-, 2-3weeks and 3months post-HSCT. Linear mixed-effects analyses showed no significant group-time interaction for global QoL (p = .199) or global distress (p = .624). However, highlighting a protective role during admission, manual participants showed minimal QoL or somatic distress change at 2-3weeks post-transplant compared with moderate-large effects for reduced QoL (d = 0.62) and increased somatic distress (d = -0.81) for TAU patients. Thematic analysis suggests the manual helped prepare patients for transplant and provided strategies to improve distress and QoL. This pilot provides preliminary evidence for the benefit of a self-help manual during hospitalisation for a HSCT. More intensive, recovery-focussed care, however, may be needed to improve psychological health in the post-hospital period. Retrospectively registered trial (ANZCTR No. 12620001165976, 6th November 2020).

Результаты трансплантации аллогенных гемопоэтических стволовых клеток при острых лейкозах у пациентов различного возраста

Результаты трансплантации аллогенных гемопоэтических стволовых клеток при острых лейкозах у пациентов различного возрастаResults of allogeneic hemopoietic stem cell transplantation in patients with acute leukemia for different age groups

320. Clinical Impact of Metagenomic Next Generation Sequencing in a Large Pediatric and Adult Cohort

Abstract Background Plasma metagenomic next-generation sequencing (mNGS) is an emerging diagnostic tool. As the clinical use of mNGS increases, efforts to better understand the role of mNGS in diagnosis and management of infectious diseases are essential. Current literature is limited to small retrospective reviewers and a prospective study therefore subject to institutional variability. Here, we aim to describe the use, sensitivity, time to diagnosis, clinical impact, and cost effectiveness of mNGS in the largest patient cohort to date. Methods We included pediatric and adult patients who had plasma mNGS testing as part of care from December 2017 through December 2021 at University of Minnesota (UMN). Patients were identified using the Karius database. Electronic medical records were reviewed for every mNGS test, recording patient demographics, underlying conditions, indications, and results within 30 days of mNGS. All cases were assessed by 2 reviewers including one board-certified infectious diseases doctor. Sensitivity of mNGS was determined relative to conventional tests. The primary end point was change in clinical management. Secondary end points included accuracy, time to diagnosis, and infectious disease consultation. UMN IRB approved this study as non human subjects research. Results 584 mNGS tests were ordered in the study period, with 203 reviews completed to date. Solid organ transplantation (SOT) (32%) was the most common underlying condition, followed by hemopoietic stem cell transplantation (HSCT) (28%). Fever (45.8%), then pulmonary findings (26%) were the most common indications for ordering mNGS. Conventional and mNGS tests identified an infectious cause of the clinical syndrome in 49% of cases, while a contaminant was found in 52% of cases. The sensitivity of mNGS in identification of infectious cause was 47%, approximately 7% more sensitive than conventional testing. Despite this increased sensitivity, mNGS changed clinical management in 20% of cases. Conclusion mNGS demonstrated superiority in accurate detection of infectious causes of clinical syndromes, however, changed clinical management in a minority of cases, suggesting timing of the mNGS test is critical. This study identified SOT and HSCT as high yield patient groups for implementation of a prospective study. Disclosures Beth K. Thielen, MD, PhD, Horizon: Advisor/Consultant|Horizon: Honoraria|Merck: Grant/Research Support.

Second Allogeneic Hematopoietic Stem Cell Transplantation for Hemophagocytic Syndrome with Engraftment Failure

This study aims to assess the efficacy of second allogeneic hemopoietic stem cell transplantation (allo-HSCT) for treating hemophagocytic syndrome with first engraftment failure. Among a total of 35 patients who underwent allo-HSCT between June 2015 and July 2021 for HLH, 10 patients who underwent a second HSCT following graft rejection were retrospectively analyzed. Various factors, such as the treatment course and outcome, the remission status, donor selection, and the conditioning regimen of patients before second allo-HSCT, were scrutinized for transplant-related complications and transplant-related mortality, as well as transplant outcomes. All the subjects have achieved complete donor engraftment, in which the neutrophils and platelets engraftment occurred in a median time of 12 d (range 10–19 d) and 24 d (range 11–97 d), respectively. Among the selected subjects, 20% of patients are diseased due to transplant-related thrombotic microangiopathy. Further, 90% of patients are diagnosed with aGVHD, in which 3 of them with grade I aGVHD, one patient with grade II aGVHD, two patients with grade III GVHD, and three patients with localized chronic GVHD. Moreover, 70% of patients showed signs of combined viral infections. Despite the complex symptoms, the overall survival rate is around 80%, with transplant-related mortality and the incidence of post-transplant GVHD of 20% and 60%, respectively. Together, our findings indicated that the second allo-HSCT showed great potential in treating hemophagocytic syndrome with engraftment failure.

CMV reactivation initiates long-term expansion and differentiation of the NK cell repertoire.

NK cells play an important role in suppression of viral replication and are critical for effective control of persistent infections such as herpesviruses. Cytomegalovirus infection is associated with expansion of 'adaptive-memory' NK cells with a characteristic CD56dimCD16bright NKG2C+ phenotype but the mechanisms by which this population is maintained remain uncertain. We studied NK cell reconstitution in patients undergoing haemopoietic stem cell transplantation and related this to CMV reactivation. NK cells expanded in the early post-transplant period but then remained stable in the absence of viral reactivation. However, CMV reactivation led to a rapid and sustained 10-fold increase in NK cell number. The proportion of NKG2C-expressing cells increases on all NK subsets although the kinetics of expansion peaked at 6 months on immature CD56bright cells whilst continuing to rise on the mature CD56dim pool. Phenotypic maturation was observed by acquisition of CD57 expression. Effective control of viral reactivation was seen when the peripheral NK cell count reached 20,000/ml. These data show that short term CMV reactivation acts to reprogramme hemopoiesis to drive a sustained modulation and expansion of the NK cell pool and reveal further insight into long term regulation of the innate immune repertoire by infectious challenge.

Patients Reported Outcomes (PROs) Are Still Unsatisfactory Among AML Long-Term Survivors: The Impact of Chronic GvHD in a Prospective Study on 15 Years Transplant Activity

Background Acute myeloid leukemia (AML) represents the main indication to allogeneic hemopoietic stem cell transplantation (HSCT) and improvement of overall survival (OS) has been a major achievement provided by this treatment option. Unfortunately, graft-versus-host disease (GvHD) still represents the main complication affecting HSCT, increasing transplant related mortality (TRM) and worsening quality of life (QoL). While the mortality impact of GvHD is well recognized, the impact on QoL is still poorly characterized. The collection of patients reported outcomes (PROs) in routine practice is limited. The most common PRO measures used are the Lee chronic GvHD (cGvHD) symptom scale, the FACT-BMT and the NIH Form B. We aimed to analyze the perception of QoL in AML long-term survivors after HSCT according to the FACT-BMT scale. Methods Our analysis consisted of a prospective single-center study in a cohort of 510 patients affected by either de novo AML or secondary AML and treated with HSCT between January 2004 and December 2019 at our Institute. Data were censored April 1st, 2022. The follow-up was performed according with our Long Term Follow Up institutional program. The FACT-BMT questionnaire was administered as a paper questionnaire. A written consent was given in accordance with the Declaration of Helsinki. Results Overall, the 2-year OS was 51% and the 5-year OS for patients alive at 2 years was 80% (95% CI - 74-85%). For patients alive and in complete remission at 2 years post-HSCT the probability of 5-year OS was 84.5% (95% CI - 78-89,2%), the 5-year TRM 6.3% (95% CI - 0.5-23.3%) without evidence of a "plateau” effect, while the 5-year relapse incidence was 12.91% (95% CI - 4.91-24.91%) reaching a plateau. Both univariate and multivariate analysis showed that age and status of disease at transplant have a significant impact on long-term survival; univariate analysis instead did not show any impact of the year of treatment and of GvHD prophylaxis. Overall, among 195 patients alive and in complete remission at last follow-up, 70 patients completed the questionnaire. PROs analysis confirmed a better perception of QoL for patients that did not experience cGvHD versus patients affected by cGvHD; no difference emerged according to age and time after transplant. Of note, patients affected by cGvHD showed worst functional well-being (p 0.0293), worst physical well-being due to side effects (p <0.0001), less satisfaction about the appearance of their body (p 0.0152) and less satisfaction about their sexual life (p 0.0445 - 10 patients preferred not to answer). Overall, among patients without cGvHD, other side effects after HSCT were not perceived worse than they had imagined, while among those with cGvHD, most patients complained about this perception (p 0.0009). Conclusion QoL in patients cured from AML by HSCT is still far from being satisfactory, most of all among patients with cGvHD. Dedicated counselling and support to address QoL is a relevant unmet medical need. Systematic evaluation of PROs will optimize the care of HSCT survivors, potentially enhancing patient-provider communication and allowing the development of measure for both prevention and treatment of GvHD.

Thromboembolic Complications PICC-Related in Adult Patients Affected By Hematologic Diseases: A 13-Years Monocentric Experience

Background: Currently, Peripheral Insertion Central Venous Catheters (PICCs) represents the device of choice for the treatment of hematologic patients because of lower risk of complications, easier management in outpatient population compared to Centrally Inserted Central Venous Catheters (CICCs) and effectiveness in performing high-risk therapy as hematopoietic stem cell transplantation. Introduction: PICC insertion and use could be characterized by the occurrence of complications, whose most dangerous are the systemic and local infections and thromboembolic (TE) manifestations. The aim of this study is to evaluate the incidence of TE complications and the risk factors associated to their development. Methods: Since the 2007, a PICC team, consisting of a hematology physician and three dedicated nurses has carried out a prospective study to evaluate complication rate and usefulness of PICC device in the hematology clinical practice. Inclusion criteria included all hematologic inpatient and outpatient who needed program of chemo-radiotherapy, support treatment and HSCT, regardless of white blood cells (WBC) and platelets (PLT) counts. All patients underwent a previous evaluation of arms vascular anatomy by ultrasonography. All implantation procedures were performed under ultrasound guide with radiographic control following insertion. The TE complications were diagnosed in clinical suspicion with venous color-doppler ultrasound and, if necessary, vascular CT scan. The therapy was performed according to local guidelines. The duration of PICC life is reported as 1000 days/PICC. The statistical analysis were performed with R software (R core team 2021). Results: From March 2007 to June 2020, 1132 PICC implantation were performed in 983 hematologic patients (545 male and 438 females). Median age was 56 years, range 15-94. The most representative diseases were non-Hodgkin Lymphoma (NHL) (332 patients, 33,8%), Hodgkin Lymphoma (HL) (276 patients, 28%), Multiple Myeloma (MM) (127 patients, 12,9%), Acute Myeloid Leukemia (AML) (107 patients, 11%). Seven hundred and eighten PICCs (63.4%) were inserted in patients that underwent a previous therapy. Nine hundred and ten PICCs (80,4%) were used for chemo-radiotherapy courses, 95 (8,4%) for support treatment, 111 (9,8%) for autologous hemopoietic stem cell transplantation (HSCT), 15 (1,3%) for allogenic HSCT, 1 for auto-allo HSCT (0.09%). PICC median life was 133 days (range 1-1257) for a total of 156485 days. Forty-two PICCs were lost at follow up and for this reason the analysis about duration and complication was performed on 1090 devices. At the time of this analysis 25 PICCs (2,3%) are still in situ and in use, 754 (69,2%) were removed for end of therapy, 94 (8,6%) for accidental withdrawals, 130 (11,9%) for death, 1 (0,1%) for patient decision. Only 86 PICCs (7,9%) were removed because of catheter related complications: 4 (0,36%) for catheter rupture, 25 (2,3%) for malfunctioning/occlusion, 11 (1%) for malposition, 7 (0,64%) for local infection, 3 (0,3%) for confirmed PICC-related sepsis 36 (3,3%) for suspected PICC-related sepsis. There were only 30 episodes (2,7%; 0,19/1000 days/PICC) of symptomatic PICC-related thrombotic complications, without need of removal. The TE complications were described in PICC inserted in patients affected by HL (11 PICCs, 36.3%), NHL (9, 30%), MM (5, 16,7%), AML (2, 6,7%), promyelocitic leukemia (2, 6,7%), non neoplastic anemia (1, 3,4%). The univariate analysis shown a strong association between the TE complications and the duration of PICC life (Tab. 1). The multivariate analysis confirm this data with a demonstration that a diagnosis of HL and the age at time of insertion could be considered as risk factors for the onset of TE disease (Tab.1). Conclusions. These data shown that the rate of TE complications in our experience in adult hematologic patients is very low, no impacting on the safety of patients and usefulness of the devices. The advanced age of patients, duration of PICC life and HL diagnosis seem to be risk factor for the onset of TE manifestations PICC-related. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of Complications of BCMA-Directed Therapy in Relapsed Multiple Myeloma: A Focused Review

Introduction: Multiple Myeloma (MM) remains incurable despite the advances made with the drugs such as proteasome inhibitors, immunomodulatory agents, antibodies, and hemopoietic stem cell transplantation (HSCT). B-cell Maturation Antigen (BCMA) is a surface receptor which can be targeted by Antibody-drug conjugates, Chimeric antigen receptor T cells (CAR-T), and Bispecific T cell engager (Bi-TE), these therapies have shown high response rates up to 70-100% in relapse-refractory MM (RRMM) (Tai et al., 2019). Despite the promising outcome, there are various adverse reactions associated with BCMA. In this focused review, we will discuss how to manage these complications. Method: We have performed literature search from PubMed and Google Scholar with the MeSH terms and keywords 'multiple myeloma', 'BCMA', 'infections', 'CRS', 'Cytopenia', 'ADC', 'CAR-T', and 'Bi-TE'. After reviewing about 150 articles, we have included the original articles in which the complication after BCMA therapy and its management were documented. Result: CRS and Immune effector cell-associated neurotoxicity syndrome (ICANS): CRS is the most common complication post-BCMA therapy, with the incidence found to be 80-100% after CAR-T cell infusion (Wang et al., 2022). Severity may vary from mild self-limiting illness to hemodynamic instability (Grade 1-IV) requiring vasopressor and ventilatory support. The cytokines mostly responsible is Interleukin-6 (IL-6), however IL-1, IL-2, IL-10, GM-CSF could also be found associated with it. Due to symptom overlap, infectious etiology should be ruled out before treating CRS. Tocilizumab is FDA approved for life-threatening CRS in patient aged two years or above, it is a monoclonal antibody that targets both membrane bound and soluble form of IL-6 receptor and competes with IL-6 to bind it (Le et al., 2018). Steroid is used in CRS refractory to tocilizumab or being administered concomitantly for high grade CRS or CRS associated with neurotoxicity. Siltuximab which binds to site I of IL-6 receptor and prevents IL-6 binding to it, is not FDA approved, however used in selective tocilizumab resistance cases or as an alternative therapy (Riegler et al., 2019). Anakinra is an IL-1 receptor antagonist, which was found to improve CRS in association with tocilizumab when compared to tocilizumab alone (Jatiani et al., 2020). Lenzilumab, is a monoclonal antibody that neutralizes granulocyte-monocyte colony stimulating factor (GM CSF), was also used in preclinical studies and found to be lessening the severity of CRS without dampening CAR-T cell function (Sterner et al., 2019). Infections: The factors which increase the risk of infection in MM patients post-BCMA therapy are >3 prior lines of therapy, B-cell aplasia, infections 30-days before CAR-T, and post CAR-T lymphopenia. To prevent infection, it is recommended to use antibacterial prophylaxis for neutropenia, to be continued for at least a month after CAR-T. Also, it is recommended to use VZV and PCP prophylaxis for 6 months and 3 months respectively (Kambhampati et al., 2022). GM-CSF support can be considered to keep absolute neutrophil count (ANC) >1000 cells/mm3 but weigh risk vs benefits as GM-CSF can increase CRS in theory. Regular monitoring of viral load and antigens are also recommended. Cytopenia: The mechanisms involved in cytopenia(s) are prior cytotoxic therapy, chemotherapy causing lymphodepletion, HSCT, or development of MDS. The mainstay of management for cytopenia(s) are supportive management with blood product transfusion to keep parameters above target, G-CSF, prophylactic anti-bacterial and anti-fungal agents in severe neutropenia. In most cases cytopenia would improve over a period of 12-months. Conclusion: Given the recent use of BCMA therapy in RRMM, there is no standard guideline on how to manage the complications associated with it. Larger studies with longer follow up needs to be conducted, to address the safety of the therapy for better patient outcome Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: A Phase 1b Study of ELA026 in Patients with Secondary Hemophagocytic Lymphohistiocytosis

Background: ELA026 is a fully human, monoclonal immunoglobulin G1 (IgG1) signal regulatory protein (SIRP)-directed antibody. SIRP is a cell surface protein expressed on cells of the myeloid lineage and T cells, which are implicated in driving pathology in hemophagocytic lymphohistiocytosis (HLH). HLH is a rare, aggressive, and life-threatening syndrome of excessive immune activation. Patients typically present with fever, hepatosplenomegaly, and pancytopenia. The disease is associated with a massive systemic inflammatory response requiring immediate treatment. Left untreated, patients progress to a clinical hyperinflammatory state that can lead to multi-organ failure, circulatory shock, and death. Secondary HLH (sHLH), the most common form of HLH, is typically triggered by malignancy, autoimmune disease, or infection. Currently, there are no approved therapies for sHLH. The HLH-94 treatment protocol (etoposide, dexamethasone, and cyclosporin) is used with variable degrees of effectiveness. Preclinical studies with ELA026 have demonstrated its ability to induce both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of human monocytes and ADCC of human SIRP+ activated T lymphocytes. Administration of ELA026 to non-human primates causes a rapid, potent, and reversible reduction of circulating monocyte, granulocyte, and T cell counts. Following washout of ELA026, reconstitution of all affected cell types to predose levels is observed within hours/days, providing evidence that bone marrow hematopoiesis is unaffected. By reducing myeloid-derived antigen presenting cells (monocytes/macrophages) and interferon gamma-producing CD8+ T cells, ELA026 has the potential to halt the initiation and progression of the inflammatory process in sHLH. Objectives: Primary objectives are to evaluate the safety of ELA026 and identify a dose for Phase 2/3 testing. Secondary objectives are to determine the efficacy (best response by 4 weeks), characterize the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects, and assess the immunogenicity of ELA026. Efficacy criteria were based on modified HLH-2004 criteria, similar to what were used in a prior pivotal trial for primary HLH (Locatelli F, et al. N Engl J Med. 2020;382(19):1811-22). Study Design: This Phase 1b, open-label, single-arm, multicenter study is investigating the safety, efficacy, PK, and PD of ELA026 following multiple intravenous (IV) doses administered in up to 24 adolescent or adult patients who are treatment naïve or who have relapsed/refractory sHLH regardless of underlying trigger (NCT05416307). Patients must be at least 12 years of age at the time of sHLH diagnosis. Patients are ineligible if they have received hemopoietic stem cell transplantation within 100 days or chimeric antigen receptor (CAR) T-cell therapy within 3 months prior to the first dose of ELA026. This study utilizes an adaptive 3+3 design, with an intra-patient dose-escalation phase and a fixed-dose phase (Figure 1). In Cohort 1, after a patient has received 3 daily IV doses at a pharmacologically active dose level, the dose will be escalated until that patient (1) demonstrates monocyte reduction and ferritin biomarker evidence of improvement, (2) develops dose-limiting toxicity; or (3) receives the maximum allowable dose. Biomarker evidence of improvement is defined as: (1) monocyte depletion ≥75% from baseline to the end of the dosing interval and (2) serum ferritin reduction ≥20% from baseline levels ≥3000 ng/mL (or if baseline ferritin levels are <3000 ng/mL, any decrease in these, along with improvement in (a) fasting triglyceride levels, (b) coagulation parameters, and/or (c) sIL2 receptor levels compared to baseline). At the completion of Cohort 1, a Data Monitoring Committee will determine the optimal fixed dose for Cohort 2 to confirm its safety and efficacy. Optional Cohorts 3 and 4 will explore less frequent dosing schedules. Subcutaneous administration also may be evaluated. Total treatment duration is 12 weeks. No formal statistical hypothesis is being tested. At the completion of Phase 1b, an appropriate dose, route of administration, and dose interval will be determined for a Phase 2/3 trial. The study is sponsored by Electra Therapeutics, Inc. Figure 1. Study SchemaFigure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated with Expansion and Maturation of NK Cells

ABSTRACT Background. Hodgkin Lymphoma (HL) Hodgkin Lymphoma (HL) is a B-Cell neoplasia characterized by a high degree of response to chemotherapy and an overall favourable outcome in responding patients. Despite the efficacy of first line therapy, however, about 30% of patients affected by HL are either refractory or eventually relapse (R/R) after first or second line therapy followed by autologous hemopoietic stem cell transplantation (ASCT). Immune checkpoint inhibitors (CI) have demonstrated clinical activity in HL patients relapsing after ASCT, although only 20% complete response (CR) rate are usually observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Aims. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI) and to investigate the lymphocyte subpopulation involved in the mechanism of response to CI in HL. Results. Seventeen patients with relapse/refractory (R/R) HL (median age 29 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 12 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 5 responding patients received ALI alone, as a control cohort. Most patients showed CMV seropositivity at the time of enrolment, without signs of active infection (positive anti-CMV IgG, negative IgM and undetectable CMV DNA). No adverse events were recorded, specifically, no immune-related toxicity was observed and none of the patients showed CMV reactivation. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR and 11/12 are alive and disease-free after a median follow-up of 33 months. The only relapse occured 23 months after last ALI. Six of the responding patients underwent subsequent allogeneic SCT in a CR status and 1 patients are currently waiting for transplantation. Two of the patients in the control arm relapsed after a median of 6 months (4-8 months) Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients (Fig.1). In detail, different patterns of NK cell development could be identified. Indeed, starting from one month after transplantation, in the group of patients undergoing ALI plus nivolumab, a relevant fraction of NK cells displayed a mature phenotype characterized by a CD56dimCD16bright expression (Fig. 1). On the contrary, in control patients, NK cells were characterized by a more immature phenotype (high frequencies of CD56brightCD16neg/dim NK cells) even at late time points (three months) after transplantation (Fig. 1). This event occurred in all the treated (ALI + nivolumab) patients analyzed (Fig. 1). Finally, PB from patients undergoing ALI + nivolumab was enriched in unconventional CD56dimCD16dim NK cells (Fig. 1). One month after transplantation, CD94/NKG2A+ KIR- NK cells were largely predominant in all patients, whereas CD94/NKG2A- KIR+ NK cells were present in low proportions. An increase of CD94/NKG2A- KIR+ subset occurred primarily in treated patients starting from t2. At t3, the significant increase of CD94/NKG2A- KIR+ NK cells occurred in the treated group but not in the control group . This event occurred in all the treated (ALI + nivolumab) patients analyzed, regardless of their serological status for HCMV, but was more evident in treated patients who were seropositive for HCMV. Remarkably, PB from HCMV seropositive patients undergoing ALI + nivolumab became enriched over time in differentiated NK cells characterized by high expression of NKG2C receptor (the activating counterpart of NKG2A), as compared to HCMV+ control patients. This subset represents the so-called "adaptive" NK cell population that usually increases during HCMV infection/reactivation. In this case, however, this event occurred in the absence of HCMV reactivation, and only in HCMV seropositive patients treated with ALI + nivolumab. Conclusions. Our data show anti-tumour activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favour the expansion of the "adaptive" NK cell compartment, especially in patients with CMV seropositivity, in the absence of CMV reactivation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis.

The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.

Systematic screening and focused evaluation for veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) following allogeneic stem cell transplant is associated with earlier diagnosis and prompt institution of defibrotide treatment.

Sinusoidal obstructive syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a potentially life-threatening complication following haemopoietic stem cell transplantation (HSCT). The availability of new drugs for malignant hematological conditions has allowed more patients to be eligible for allogeneic haematopoietic stem cell transplants, which has translated into a significant proportion of transplant patients having multiple risk factors for VOD/SOS. Based on these considerations, we undertook a dedicated weekly VOD/SOS ward round, aiming to facilitate early diagnosis of VOD/SOS and pre-emptively identify patients at risk, where a careful evaluation of differential diagnosis is essential. Herein, we present the results of our VOD/SOS ward round; between September 2020 and April 2022, 110 consecutive patients were evaluated in a focused VOD/SOS ward round. From the 110 patients, 108 had undergone HSCT and had at least one known risk factor for developing VOD/SOS. The median number of risk factors present in the VOD/SOS group and non-VOD/SOS group was five (range: three to six) and three (range: zero to seven), respectively. Late-onset VOD/SOS was diagnosed in 45% of our patients. The early identification of patients with multiple risk factors for VOD/SOS allowed an earlier diagnosis and the administration of defibrotide on the same day of diagnosis, which was two days earlier than our previous experience prior to the implementation of this protocol.

Incidence of chronic renal injury in patients undergoing autologous stem cell transplant therapy.

Haemopoietic stem cell transplant (HSCT) is a well-established treatment option for many haematologic immunologic and oncologic diseases, allowing the safe administration of high-dose chemotherapy. Increased risk of acute renal injury is associated with HSCT; however, the risk of chronic kidney injury in autologous HSCT remains unclear. This cohort study investigates the incidence of chronic renal injury and its predisposing factors in a single-centre population of 139 patients who underwent autologous HSCT. Estimated glomerular filtration rate (eGFR) was measured at baseline and at 3, 6, 12 and 24 months following autologous stem cell reinfusion and used as a marker of renal dysfunction. A significant reduction in mean eGFR of patients was observed from baseline (80.62 ± 2.97 mL/min) to 24 months (71.54 ± 4.14 mL/min), independent of primary diagnosis (P= 0.0019). At baseline, 12% of the cohort had stage 3 or worse chronic renal injury and this increased to 38% by 24 months. By univariate analysis, age at baseline greater than the mean of 58 years and the occurrence of acute kidney injury during the peritransplant period emerged as predictive factors for the development of chronic kidney disease at 24 months. The current results indicate there is an increased incidence of chronic renal injury in patients who have undergone autologous peripheral blood haemopoietic stem cell transplantation therapy and this injury is potentiated by the autologous stem cell transplant procedure.

Poster: CT-132 Outcome of Sex-Mismatched Allogeneic Hemopoietic Stem Cell Transplantation from Human Leukocyte Antigen–Identical Sibling Donors in Patients With Hematologic Diseases

Poster: CT-132 Outcome of Sex-Mismatched Allogeneic Hemopoietic Stem Cell Transplantation from Human Leukocyte Antigen–Identical Sibling Donors in Patients With Hematologic Diseases

CT-132 Outcome of Sex-Mismatched Allogeneic Hemopoietic Stem Cell Transplantation from Human Leukocyte Antigen–Identical Sibling Donors in Patients With Hematologic Diseases

Hematopoietic stem cell transplantation is a procedure aiming to cure hematologic diseases. However, graft-versus-host disease (GVHD) and disease relapse/failure are common side effects of this treatment. Sex-mismatched transplantation, particularly with female donors and male patients, is known to be associated with higher incidence of GVHD or lower incidence of survival. This is caused by the antibodies against minor histocompatibility antigens found on the Y chromosome of the male recipient, which were found to be associated with increased risk of chronic GVHD and non-relapse mortality. The study aimed to determine the incidence of acute and chronic GVHD, overall survival, and non-relapse mortality when male patients received stem cells from female matched sibling donors in allogeneic hematopoietic stem cell transplantation. Retrospective study over 8 years. Nasser Institute Hospital. In this study, patients were divided into 2 groups. Group 1: female donors to male patients (245 patients). Group 2: male donors to female patients (186 patients) and same-sex donors and patients (506 patients). The median age was 20 years (7 months-60 years). The outcome of transplants in the female-to-male group was compared with that of the male-to-female and same-sex group. Overall survival, incidence of acute and chronic GVHD, non-relapse mortality, and relapse/failure rate. Overall survival was 68.6% in group 1 compared to 69.5% in group 2 (P=0.5). Acute GVHD was 24% in group 1 compared to 19.6% in group 2 (P=0.1). Chronic GVHD was 15.1% in group 1 compared to 9.6% in group 2 (P=0.02). Non-relapse mortality was 27.7% in group 1 compared to 25.7% in group 2 (P=0.5). Relapse/failure rate was 4.9% in group 1 compared to 6.5% in group 2 (P=0.3). Allogeneic stem cell transplantation for male patients from female donors can be associated with a significantly higher rate of chronic GVHD but a lower incidence of relapse/failure.

Relationship Between Markers of the Acute Phase of Inflammation, Parameters of Blood Lipid Composition and Intracardiac Hemodynamics During Chemotherapy in Patients With Multiple Myeloma.

Aim To evaluate in a pilot study time-related changes in the clinical state, indexes of the acute phase of inflammation, parameters of blood lipid profile, intracardiac hemodynamics, and disorders of cardiac rhythm/conduction in patients who are not candidates for autologous hemopoietic stem cell transplantation, during three bortezomib-containing chemotherapy courses (VCD) followed by a correlation analysis.Material and methods This pilot study included 20 patients diagnosed with myeloma, who were not candidates for autologous hemopoietic stem cell transplantation and who had undergone three courses of VCD chemotherapy (bortezomib, cyclophosphamide and dexamethasone). In addition to mandatory examinations, measurement of blood lipid profile, transthoracic echocardiography (EchoCG), and 24-h Holter electrocardiogram (ECG) monitoring were performed for all participants before and after a specific therapy.Results Following three bortezomib-containing courses of chemotherapy, patients of the study group had significant increases in the neutrophil-lymphocyte ratio (NLR) (1.6±0.2 and 2.5±0.4; р=0.05), cholesterol concentration (4.8±1.1 and 5.6±1.1 mmol/l, р=0.05), and low-density lipoprotein concentration (2.8±0.4 and 3.5±0.8 mmol/l, р=0.02). In comparing the changes in parameters of intracardiac hemodynamics, criteria for genuine cardiotoxicity were not met, however, a tendency to emergence/progression of myocardial diastolic dysfunction was noted. No clinically significant disorders of cardiac rhythm/conduction were observed. The correlation analysis performed prior to the start of chemotherapy, showed significant strong, direct correlations between the C-protein concentration and left atrial (LA) volume (r=0.793; p=0.006), right atrial (RA) volume (r=0.857; p=0.002), left ventricular (LV) end-diastolic dimension (EDD) (r=0.589; p=0.043), and LV end-diastolic volume (EDV) (r=0.726; p=0.017). Following the specific treatment, significant, medium-power and strong correlations were found between NLR and EDV (r= -0.673; p=0.033), NLR and end systolic volume (ESV) (r= -0.710; p=0.021), respectively. Significant direct correlations were found between the bortezomib dose per one injection and the serum concentration of triglycerides following the treatment (r=0.78; p=0.05); a single bortezomib dose and parameters of intracardiac hemodynamics: LA (r=0.71; p=0.026), RA (r=0.74; p=0.014), EDD (r=0.837; p=0.003), EDV (r=0.749; p=0.013), ESV (r=0.553; p=0.049).Conclusion For the first time, a comprehensive evaluation was performed in patients with multiple myeloma, including the dynamics of blood lipid profile, intracardiac hemodynamics and disorders of cardiac rhythm/conduction during bortezomib-containing antitumor therapy, with an analysis of correlation with levels of acute inflammation phase markers. Although in the observation window for genuine cardiotoxicity, clinically significant cardiovascular complications were not detected, the found correlations may evidence a potential role of systemic inflammation activity in myocardial remodeling in the studied patient cohort.

Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants.

Simple SummaryHigh-risk neuroblastomas (HR-NB) are malignant tumors of childhood that are treated with a very aggressive and life-threatening approach; this includes autologous hemopoietic stem cell transplantation (HSCT) and the infusion of a mAb targeting the GD2 tumor-associated antigen. Although the current treatment provided benefits, the 5-year overall survival remains below 50% due to relapses and refractoriness to therapy. Thus, there is an urgent need to ameliorate the standard therapeutic protocol, particularly improving the immune-mediated anti-tumor responses. Our review aims at summarizing and critically discussing novel immunotherapeutic strategies in HR-NB, including NK cell-based therapies and HLA-haploidentical HSCT from patients’ family.High-risk neuroblastomas (HR-NB) still have an unacceptable 5-year overall survival despite the aggressive therapy. This includes standardized immunotherapy combining autologous hemopoietic stem cell transplantation (HSCT) and the anti-GD2 mAb. The treatment did not significantly change for more than one decade, apart from the abandonment of IL-2, which demonstrated unacceptable toxicity. Of note, immunotherapy is a promising therapeutic option in cancer and could be optimized by several strategies. These include the HLA-haploidentical αβT/B-depleted HSCT, and the antibody targeting of novel NB-associated antigens such as B7-H3, and PD1. Other approaches could limit the immunoregulatory role of tumor-derived exosomes and potentiate the low antibody-dependent cell cytotoxicity of CD16 dim/neg NK cells, abundant in the early phase post-transplant. The latter effect could be obtained using multi-specific tools engaging activating NK receptors and tumor antigens, and possibly holding immunostimulatory cytokines in their construct. Finally, treatments also consider the infusion of novel engineered cytokines with scarce side effects, and cell effectors engineered with chimeric antigen receptors (CARs). Our review aims to discuss several promising strategies that could be successfully exploited to potentiate the NK-mediated surveillance of neuroblastoma, particularly in the HSCT setting. Many of these approaches are safe, feasible, and effective at pre-clinical and clinical levels.

Centre-based comparison of double versus single prevention strategy on transfusion-transmitted cytomegalovirus in at-risk haemopoietic stem cell transplant patients and a state survey on cytomegalovirus-seronegative ordering practises.

Universal leucocyte depletion reduces the risk of transfusion-transmitted cytomegalovirus; however, many clinicians still prescribe cytomegalovirus seronegative units. Our retrospective study aims to confirm the low risk of transfusion-transmitted cytomegalovirus with leucocyte depletion alone and demonstrate the ongoing variability in cytomegalovirus seronegative transfusion prescribing. Over a 9-year period (July 2009-July 2018), occurrences of transfusion transmitted cytomegalovirus in cytomegalovirus seronegative donor/recipient haemopoietic stem cell transplant pairs were compared at one allogeneic haemopoietic stem cell transplant centre providing cytomegalovirus seronegative blood products and leucocyte depletion (double prevention) versus another providing leucocyte depletion only (single prevention). Retrospective chart audit identified patient demographics, blood product exposure and cytomegalovirus infection by polymerase chain reaction. A separate audit examined cytomegalovirus seronegative blood product ordering in a broader range of hospital types. We identified 122 and 66 cytomegalovirus-negative donor/recipient haemopoietic stem cell transplant pairs using double and single transfusion prevention strategy respectively. Transfusion exposure to red cells and pooled platelets was similar, although more apheresis platelets were used in the double prevention group. The cytomegalovirus infection rate was 3 (2.4%) and zero in the double and single prevention groups respectively. Cytomegalovirus seronegative unit ordering was not limited to hospitals with obstetric or neonatal populations, suggesting ongoing reliance of cytomegalovirus seronegative units outside this population. The analysis suggests a double prevention strategy does not provide additional protection against transfusion-transmitted cytomegalovirus. There is ongoing variability in the acceptance of leucocyte depletion alone despite the low risk of cytomegalovirus infection.