Donor selection for allogenic hemopoietic stem cell transplantation: clinical and ethical considerations

Allogenic hematopoietic progenitor cell transplantation (allo-HSCT) is an established treatment for many diseases. Stem cells may be obtained from different sources: mobilized peripheral blood stem cells, bone marrow, and umbilical cord blood. The progress in transplantation procedures, the establishment of experienced transplant centres, and the creation of unrelated adult donor registries and cord blood banks gave those without an human leucocyte antigen- (HLA-) identical sibling donor the opportunity to find a donor and cord blood units worldwide. HSCT imposes operative cautions so that the entire donation/transplantation procedure is safe for both donors and recipients; it carries with it significant clinical, moral, and ethical concerns, mostly when donors are minors. The following points have been stressed: the donation should be excluded when excessive risks for the donor are reasonable, donors must receive an accurate information regarding eventual adverse events and health burden for the donors themselves, a valid consent is required, and the recipient’s risks must be outweighed by the expected benefits. The issue of conflict of interest, when the same physician has the responsibility for both donor selection and recipient care, is highlighted as well as the need of an adequate insurance protection for all the parties involved

Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell

Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft

Genetic Relationships and Therapeutic Options for Relapsed Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of cancer among children and can be lethal to the adult population. Though 80% of patients with ALL reach complete remission after treatment, about 20% of those diagnosed fail to remain cancer-free. Genetic rearrangements are the hallmark of relapsed ALL, but the mechanism by which these rearrangements occur is still unclear. Recent research suggests these mutations may be detectable during initial diagnosis. If researchers are able to accurately assess the probability of relapse during diagnosis by analyzing the genome of the leukemic cells, the likelihood of administering effective therapy would increase. Providing patients with a more appropriate therapy early on may prevent relapse altogether or increase survival rates after treatment for relapsed ALL patients

Function, Adjustment, Quality of Life and Symptoms (FAQS) in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Survivors: A Study Protocol

<p>Abstract</p> <p>Background</p> <p>The population of survivors following allogeneic HSCT continues to increase, and yet their experiences of recovery and long-term survivorship have not been fully characterized. This paper presents a study protocol examining over time the functional status, psychosocial adjustment, health-related quality of life, and symptom experience of survivors who have undergone allogeneic transplantation. The aims of the study are to: 1) explore the patterns of change in these health outcomes during the survivorship phase; 2) characterize subgroups of survivors experiencing adverse outcomes; and 3) examine relationships among outcomes and demographic and clinical factors (such as age, graft-versus-host disease (GVHD), and disease relapse).</p> <p>Methods</p> <p>In this longitudinal observational study, adults who survive a minimum of 3 years from date of allogeneic transplantation complete a series of questionnaires annually. Demographic and clinical data are collected along with a series of patient-reported outcome measures, specifically: 1) Medical Outcomes Study SF- 36; 2) Functional Assessment of Chronic Illness Therapy (FACIT) - General, 3) FACIT-Fatigue; 4) FACIT- Spiritual; 5) Psychosocial Adjustment to Illness Scale; 6) Rotterdam Symptom Checklist-Revised; and 7) Pittsburgh Sleep Quality Index.</p> <p>Conclusions</p> <p>This study will provide multidimensional patient-reported outcomes data to expand the understanding of the survivorship experience across the trajectory of allogeneic transplantation recovery. There are a number of inherent challenges in recruiting and retaining a diverse and representative sample of long-term transplant survivors. Study results will contribute to an understanding of outcomes experienced by transplant survivors, including those with chronic GVHD, malignant disease relapse, and other late effects following allogeneic transplantation.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00128960">NCT00128960</a></p

Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis

Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT). Graft-versus-host disease (GVHD) is another complication of HSCT that may modify the risk of VTE. Our objective was to explore the incidence of VTE (deep venous thrombosis and pulmonary embolism) following HSCT and to evaluate its association with GVHD. A comprehensive search of Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus was conducted to search for both retrospective and prospective HSCT studies which had reported VTE. Random-effects meta-analysis was used to pool incidence rates. We included 17 studies reporting on allogeneic- and 10 on autologous-HSCT; enrolling 6693 patients; of which 5 were randomized. The overall incidence of VTE after HSCT was 5%(4-7%). Incidence in allogeneic-HSCT was 4%(2-6%) and in autologous-HSCT was 4%(1-15%). Eleven and nine studies reported data on acute and chronic GVHD, respectively. The incidence of VTE in chronic GVHD was 35%(20-54%), whereas in acute GVHD it was 47%(32-62%). Based on the results of this meta-analysis, VTE is a fairly common complication after HSCT, emphasizing the importance of assimilating guidelines for both treatment and prophylaxis in this patient population

Understanding patient quality of life following haematopoietic cell transplant

Purpose: The purpose of this study was to explore how haematopoietic cell transplantation (HCT) recipients define quality of life (QoL) and the impact of receiving a stem cell transplant. Methods: Qualitative one-on-one semi-structured interviews were conducted with patients aged ≥ 18 years who had received HCT. Interviews were audio recorded, transcribed verbatim and thematically analysed using NVivo 14 software. A patient advisory group (n = 6 patients) co-designed the qualitative interview study and were involved in developing the initial coding framework and themes generated. Results: Data saturation was reached after 21 interviews (median age 45 years, range 26–71 years). Participants described a change in perspective about the meaning of QoL post-transplant and having to adapt to a ‘new normal’. Specifically, patients described how being immunocompromised post HCT negatively affected social, emotional and occupational QoL. Participants described facing a new, unfamiliar reality post-transplant and a feeling of being un-prepared for the long-term impact of HCT. Conclusion: Patients require support to cope with continuously changing physical, social, emotional and occupational challenges. Supportive care interventions should be designed to address the impact of being immunocompromised

Cord blood banking – bio-objects on the borderlands between community and immunity

Umbilical cord blood (UCB) has become the focus of intense efforts to collect, screen and bank haematopoietic stem cells (HSCs) in hundreds of repositories around the world. UCB banking has developed through a broad spectrum of overlapping banking practices, sectors and institutional forms. Superficially at least, these sectors have been widely distinguished in bioethical and policy literature between notions of the ‘public’ and the ‘private’, the commons and the market respectively. Our purpose in this paper is to reflect more critically on these distinctions and to articulate the complex practical and hybrid nature of cord blood as a ‘bio-object’ that straddles binary conceptions of the blood economies. The paper draws upon Roberto Esposito’s reflections on biopolitics and his attempt to transcend the dualistic polarisations of immunity and community, or the private and the public. We suggest that his thoughts on immunitary hospitality resonate with many of the actual features and realpolitik of a necessarily internationalised and globally distributed UCB ‘immunitary regime’

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade 65II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and 648/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence

Conceptualizing the psychosocial elements that should be assessed in candidates for hematopoietic cell transplantation: social workers\u27 and psychologists\u27 perspectives.

Background: In the United States, approximately 23,000 hematopoietic cell transplantations (HCT), also known as a bone marrow transplant, are performed annually. Patients who undergo HCT are among the most acutely ill and medically vulnerable oncology populations. Given the arduous nature of HCT, patients undergo an extensive pre-transplant evaluation that typically includes psychosocial assessment. The literature lacks a well-defined conceptual framework of the psychosocial elements that should be assessed in HCT candidates. This has led to practice variation, which has in turn inhibited high quality psychosocial research. Method: Social workers and psychologists in HCT were recruited to participate in a concept mapping study to elucidate the conceptual domain of psychosocial elements that should be assessed in candidates pre-HCT. Concept mapping is a mixed methodology that uses quantitative methods (multidimensional scaling and hierarchical cluster analysis) to analyze qualitative data. It results in a series of maps that depict the group’s composite thinking about the conceptual domain. Results: Participants brainstormed 114 distinct psychosocial elements and conceptualized the elements into 12 distinct clusters: Transplant Mindset, Support System, Caregiver, Lodging and Transportation, Financial and Legal, Work, Demographic Characteristics, Mental Health, Communication, Education and Resource Needs, Physical Functioning, and Cognition. Analyses of importance ratings showed that that participants who use standardized psychosocial risk rating scales in their practice did not prioritize these clusters differently than those who do not use risk rating scales in their practice. Conclusion: Findings show that the domain of psychosocial elements is broad and multi-dimensional. The conceptualization converges with the literature in many respects but also contains noteworthy divergences from the current literature. Divergences are of particular interest since the perspectives of these psychosocial professionals have been largely absent from the literature. The maps and findings may be used to inform the development of a pre-HCT psychosocial assessment protocol that would constitute a high quality practice standard and produce consistent data for psychosocial research

Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP) : a randomised, open-label, phase 3, non-inferiority trial

Background: Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. Methods: To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1–3 plus mitoxantrone (10 mg/m2 intravenously) on days 3–5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov , NCT02461537. Findings: 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI –5·8 to 12·6) for the ITT population and 2·7% (–6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7–64) versus 42 days (27–121, U test p<0·0001), respectively. Interpretation: Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia