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Background: Healthy volunteer registry donors have become the backbone of stem cell transplantation programs. While most registrants will never become actual donors, a small minority are called upon twice, most commonly for the same patient because of poor graft function. Anecdotal evidence provides no hard reasons to disallow second-time mobilized apheresis, but few centers have treated enough two-time donors for definitive conclusions. Moreover, for reasons unknown, the efficiency of G-CSF varies greatly between donations.
Methods: Comparison of outcomes of first vs. second donations can formally confirm G-CSF responsiveness as intrinsically, likely genetically, determined. In our database, we identified 60 donors (1.3%) who received two cycles of G-CSF 24 days to 4 years apart and systematically compared mobilization outcomes.
Results: First and second mobilization and collection proceeded without severe or unusual adverse effects. First-time mobilization efficiency was highly predictive of second-time mobilization. Neither mobilization efficiency nor time lag between donations affected the similarity of first- and second-time mobilization outcomes.
Conclusions: With the caveat that only donors with an unremarkable first donation were cleared for a second, our data indicate that a second donation is feasible, equally tolerable as a first donation, and efficient. Moreover, the data strongly support the notion of donor-intrinsic variables dictating mobilization response and argue against relevant damage to the stem cell compartment during mobilization with rhG-CSF.
Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance through the release of small extracellular vesicles (sEVs). In contrast, we show here that BMM deficiency of pleckstrin homology domain family M member 1 (PLEKHM1), which serves as a hub between fusion and secretion of intracellular vesicles and is important for vesicular secretion in osteoclasts, accelerates murine BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) via regulation of the cargo of sEVs released by BMM-derived mesenchymal stromal cells (MSCs). PLEKHM1-deficient MSCs and their sEVs carry increased amounts of syntenin and syndecan-1, resulting in a more immature B-cell phenotype and an increased number/function of leukemia-initiating cells (LICs) via focal adhesion kinase and AKT signaling in B-ALL cells. Ex vivo pretreatment of LICs with sEVs derived from PLEKHM1-deficient MSCs led to a strong trend toward acceleration of murine and human BCR-ABL1+ B-ALL. In turn, inflammatory mediators such as recombinant or B-ALL cell–derived tumor necrosis factor α or interleukin-1β condition murine and human MSCs in vitro, decreasing PLEKHM1, while increasing syntenin and syndecan-1 in MSCs, thereby perpetuating the sEV-associated circuit. Consistently, human trephine biopsies of patients with B-ALL showed a reduced percentage of PLEKHM1+ MSCs. In summary, our data reveal an important role of BMM-derived sEVs for driving specifically BCR-ABL1+ B-ALL, possibly contributing to its worse prognosis compared with BCR-ABL1− B-ALL, and suggest that secretion of inflammatory cytokines by cancer cells in general may similarly modulate the tumor microenvironment.
Background: The ability to approximate intra-operative hemoglobin loss with reasonable precision and linearity is prerequisite for determination of a relevant surgical outcome parameter: This information enables comparison of surgical procedures between different techniques, surgeons or hospitals, and supports anticipation of transfusion needs. Different formulas have been proposed, but none of them were validated for accuracy, precision and linearity against a cohort with precisely measured hemoglobin loss and, possibly for that reason, neither has established itself as gold standard. We sought to identify the minimal dataset needed to generate reasonably precise and accurate hemoglobin loss prediction tools and to derive and validate an estimation formula.
Methods: Routinely available clinical and laboratory data from a cohort of 401 healthy individuals with controlled hemoglobin loss between 29 and 233 g were extracted from medical charts. Supervised learning algorithms were applied to identify a minimal data set and to generate and validate a formula for calculation of hemoglobin loss.
Results: Of the classical supervised learning algorithms applied, the linear and Ridge regression models performed at least as well as the more complex models. Most straightforward to analyze and check for robustness, we proceeded with linear regression. Weight, height, sex and hemoglobin concentration before and on the morning after the intervention were sufficient to generate a formula for estimation of hemoglobin loss. The resulting model yields an outstanding R2 of 53.2% with similar precision throughout the entire range of volumes or donor sizes, thereby meaningfully outperforming previously proposed medical models.
Conclusions: The resulting formula will allow objective benchmarking of surgical blood loss, enabling informed decision making as to the need for pre-operative type-and-cross only vs. reservation of packed red cell units, depending on a patient’s anemia tolerance, and thus contributing to resource management.
Background: Safety, tolerability and efficacy of granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem and progenitor cells (HSPCs) from healthy donors have been conclusively demonstrated. This explicitly includes, albeit for smaller cohorts and shorter observation periods, biosimilar G-CSFs. HSPC donation is non-remunerated, its sole reward being “warm glow”, hence harm to donors must be avoided with maximal certitude. To ascertain, therefore, long-term physical and mental health effects of HSPC donation, a cohort of G-CSF mobilized donors was followed longitudinally.
Methods: We enrolled 245 healthy volunteers in this bi-centric long-term surveillance study. 244 healthy volunteers began mobilization with twice-daily Sandoz biosimilar filgrastim and 242 underwent apheresis after G-CSF mobilization. Physical and mental health were followed up over a period of 5-years using the validated SF-12 health questionnaire.
Results: Baseline physical and mental health of HSPC donors was markedly better than in a healthy reference population matched for ethnicity, sex and age. Physical, but not mental health was sharply diminished at the time of apheresis, likely due to side effects of biosimilar G-CSF, however had returned to pre-apheresis values by the next follow-up appointment after 6 months. Physical and mental health slightly deteriorated over time with kinetics reflecting the known effects of aging. Hence, superior physical and mental health compared to the general healthy non-donor population was maintained over time.
Conclusions: HSPC donors are of better overall physical and mental health than the average healthy non-donor. Superior well-being is maintained over time, supporting the favorable risk–benefit assessment of volunteer HSPC donation.
Trial registration National Clinical Trial NCT01766934
Background: Because of limitations of transportation imposed by the COVID-19 pandemic, current recommendation calls for cryopreservation of allogeneic stem cell transplants before patient conditioning. A single cell therapy laboratory was selected to function as the central cryopreservation hub for all European registry donor transplants intended for the Australian-Pacific region. We examined properties of these transplants to ascertain how quality is maintained.
Methods: We analyzed 100 pandemic-related allogeneic mobilized blood-derived stem cell apheresis products generated at 30 collection sites throughout Europe, shipped to and cryopreserved at our center between April and November of 2020. Products were shipped in the cool, subsequently frozen with DMSO as cryoprotectant. Irrespective of origin, all products were frozen within the prescribed shelf-life of 72 h.
Results: Prior to cryopreservation, viable stem cell and leukocyte count according to the collection site and our reference laboratory were highly concordant (r2 = 0.96 and 0.93, respectively) and viability was > 90% in all instances. Median nominal post-thaw recovery of viable CD34+ cells was 42%. Weakly associated with poorer CD34+ cell recovery was higher leukocyte concentration, but not time lag between apheresis or addition of cryopreservant, respectively, and start of freezing. The correlation between pre- and post-thaw CD34+ cell dose was high (r2 = 0.85), hence predictable. Neutrophil and platelet engraftment were prompt with no evidence of dose dependency within the range of administered cell doses (1.31–15.56 × 106 CD34+ cells/kg).
Conclusions: General cryopreservation of allogeneic stem cell transplants is feasible. While more than half of the CD34+ cell content is lost, the remaining stem cells ensure timely engraftment.
Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.
The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.
High-risk rhabdomyosarcoma (RMS) occurring in childhood to young adulthood is associated with a poor prognosis; especially children above the age of 10 with advanced stage alveolar RMS still succumb to the disease within a median of 2 years. The advent of chimeric antigen receptor (CAR)-engineered T cells marked significant progress in the treatment of refractory B cell malignancies, but experience for solid tumors has proven challenging. We speculate that this is at least in part due to the poor quality of the patient's own T cells and therefore propose using CAR-modified cytokine-induced killer (CIK) cells as effector cells. CIK cells are a heterogeneous population of polyclonal T cells that acquire phenotypic and cytotoxic properties of natural killer (NK) cells through the cultivation process, becoming so-called T-NK cells. CIK cells can be genetically modified to express CARs. They are minimally alloreactive and can therefore be acquired from haploidentical first-degree relatives. Here, we explored the potential of ERBB2-CAR-modified random-donor CIK cells as a treatment for RMS in xenotolerant mice bearing disseminated high-risk RMS tumors. In otherwise untreated mice, RMS tumors engrafted 13–35 days after intravenous tumor cell injection, as shown by in vivo bioluminescence imaging, immunohistochemistry, and polymerase chain reaction for human gDNA, and mice died shortly thereafter (median/range: 62/56–66 days, n = 5). Wild-type (WT) CIK cells given at an early stage delayed and eliminated RMS engraftment in 4 of 6 (67%) mice, while ERBB2-CAR CIK cells inhibited initial tumor load in 8 of 8 (100%) mice. WT CIK cells were detectable but not as active as CAR CIK cells at distant tumor sites. CIK cell therapies during advanced RMS delayed but did not inhibit tumor progression compared to untreated controls. ERBB2-CAR CIK cell therapy also supported innate immunity as evidenced by selective accumulation of NK and T-NK cell subpopulations in disseminated RMS tumors, which was not observed for WT CIK cells. Our data underscore the power of heterogenous immune cell populations (T, NK, and T-NK cells) to control solid tumors, which can be further enhanced with CARs, suggesting ERBB2-CAR CIK cells as a potential treatment for high-risk RMS.
Background and Objectives: Red blood cell (RBC) transfusions are needed by almost every acute myeloid leukaemia (AML) patient undergoing induction chemotherapy and constitute a cornerstone in supportive measures for cancer patients in general. Randomized controlled trials have shown non‐inferiority or even superiority of restrictive transfusion guidelines over liberal transfusion guidelines in specific clinical situations outside of medical oncology. In this study, we analysed whether more restrictive RBC transfusion reduces blood use without affecting hard outcomes.
Materials and Methods: A total of 352 AML patients diagnosed between 2007 and 2018 and undergoing intensive induction chemotherapy were included in this retrospective analysis. In the less restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 8 g/dl (2007–2014). In the restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 7 g/dl (2016–2018). Liberal transfusion triggers were never endorsed.
Results: A total of 268 (76·1%) and 84 (23·9%) AML patients fell into the less restrictive and restrictive transfusion groups, respectively. The less restrictive transfusion group had 1 g/dl higher mean haemoglobin levels, received their first RBC transfusions earlier and needed 1·5 more units of RBC during the hospital stay of induction chemotherapy. Febrile episodes, C‐reactive protein levels, admission to the intensive care unit, length of hospital stay as well as response and survival rates did not differ between the two cohorts.
Conclusion: From our retrospective analysis, we conclude that a more restrictive transfusion trigger does not affect important outcomes of AML patients. The opportunity to test possible effects of the more severe anaemia in the restrictive transfusion group on quality of life was missed.