Unrelated Volunteer Donors Research Articles

Long-term outcomes of peripheral blood stem cell unrelated donors mobilized with filgrastim

AbstractAllogeneic hematopoietic cell transplantation is a life-saving procedure used to treat a variety of devastating diseases. It requires hematopoietic stem cells collected via filgrastim-mobilized peripheral blood stem cells (PBSCs) or bone marrow (BM) harvest from volunteer unrelated donors (URDs). There is a paucity of safety data regarding donors’ long-term adverse events. This prospective, observational study combined PBSC donors enrolled in the NMDP Investigational New Drug trial and BM donors between 1 July 1999 and 30 September 2015. The primary objective was to describe the long-term incidence of myeloid malignancies. The secondary objectives included describing the long-term incidence of lymphoid malignancies, nonhematologic malignancies, autoimmune disorders, and thrombotic events. A total of 21 643 donors (14 530 PBSCs and 7123 BM) were included. The incidence rate of myeloid disorders per 100 000 person-years in donors of PBSCs was 2.53 (95% confidence interval [CI], 0.82-7.84) and in donors of BM, it was 4.13 (95% CI, 1.33-12.8). The incidence rate ratio of PBSCs/BM donors was 0.61 (95% CI, 0.12-3.03; P = .55). The incidence of other malignancies, autoimmunity, and thrombosis did not differ between the donor types. This comprehensive study of the long-term effects of filgrastim in URDs of PBSCs provides strong evidence that donors who receive filgrastim are not at an increased risk of these events compared with BM donors. It also provides reassurance to current donors undergoing stem cell mobilization as well as individuals considering joining stem cell registries, such as NMDP.

Racial/ethnic disparities in availability of volunteer unrelated donors for allogeneic transplantation

AbstractDespite the global unrelated donor (URD) registry size, the degree to which URD availability is a transplant barrier is not established. We evaluated the availability of 3,843 URDs requested for 455 diverse adult patients (predominantly with acute leukemia). URDs for non-Europeans were more likely to be domestic and had markedly lower Donor Readiness scores. Of URDs requested for confirmatory HLA-typing (CT) alone (ie, without simultaneous workup), 1,894 of 3,529 (54%) were available. Availability of domestic URDs was 45%. Donor Readiness score was highly predictive of CT availability. More non-European patients (n = 120) than Europeans (n = 335) had >10 URDs requested and <5 available. Of workup requests (after CT or CT-workup), <70% (604/889 [68%]) were available. More non-Europeans had <2 URDs available. URD availability for CT was markedly worse for non-Europeans, with availabilities for African, non-Black Hispanic, and Asian patients being 150/458 (33%), 120/258 (47%), and 119/270 (44%), respectively, with further decrements in URD workup availability. Our data suggest the functional size of the URD pool is much smaller than appreciated, mandating major operational changes for transplant centers and donor registries. Likelihood of donor availability should have a high priority in donor selection. Considering patient ancestry and URD Donor Readiness scores, centers should pursue, and registries permit, simultaneous pursuit of many URDs and abandon futile searches. Patients should be informed about their likelihood of donor availability and alternative options. Finally, although registries should address high URD attrition and speed procurement, use of all HLA-disparate graft types is needed to facilitate timely transplant for all.

British Columbia Experience in Allogeneic Stem Cell Transplantation for Myelofibrosis with or without Pre-Transplant Ruxolitinib

Introduction Allogeneic stem cell transplantation (AlloHSCT) remains the only potentially curative treatment for myelofibrosis (MF). It confronts many challenges stemming from the older age of the typical patients and their age-related comorbidities, as well as disease-specific factors such as splenomegaly and hostile marrow microenvironment, which raise concerns for delayed engraftment and graft failure. Methods We performed a retrospective review of the 58 adult patients who received AlloHSCT for MF in British Columbia, Canada, in the 20-year period between January 2001 and December 2020. Data pertaining to patient demographics, disease characteristics, treatment/transplant details and clinical outcomes were gathered from the available paper and electronic records. Relapse-free survival (RFS) was defined as the time between the day of the transplant and the day of disease relapse or death from any cause. Overall survival (OS) was defined as the time between the day of the transplant and death from any cause. Patients who did not have an event during follow up were censored at the time of the last known follow up. Survival analysis was performed by Kaplan-Meier survival estimator and log-rank test, using Stata version 16.1 (Texas, USA). Results The median age of the cohort was 56 years (range 26-68), with 36% being 60 years old or older. The male to female ratio was 1.6:1. The median Karnofsky Performance Status index was 80 (range 70-100) and the median age-adjusted HCT-specific Comorbidity Index was 2 (range 0-5). The pre-transplant DIPPS plus risk category was: high in 13 patients (22%); intermediate-2 in 29 (50%); intermediate-1 in 15 (26%); and low in 1 (2%). 19/58 (33%) had a peripheral blast percentage greater than 2%. 51/58 (88%) had grade 3 fibrosis seen on the pre-AlloHSCT bone marrow biopsy. 27/57 (47%) patients were transfusion-dependent for pRBC and/or platelets. 28/54 (52%) evaluable patients had a normal karyotype and 6/54 (11%) a complex karyotype. Sixteen patients (28%) had a myeloid gene panel performed by PCR; the most commonly seen variants were ASXL1 (10 patients) and TET2 (5 patients). The median number of variants seen in a single patient was 3 (range 0-5). 42/58 (72%) patients received myeloablative conditioning before AlloHSCT. The donor type was: a volunteer unrelated donor in 54%; a matched sibling in 42%; and an alternative source (double cord or haploidentical donor) in 4%. Peripheral blood stem cells were used in 93% of the AlloHSCT. 24/58 (41%) patients received ruxolitinib pre-AlloHSCT (starting in June 2012) for a median duration of 10 months (range 1-44); 17/24 (71%) of the recipients had a clinical response to ruxolitinib but 3 had lost the response before their AlloHSCT. One patient had stopped ruxolitinib due to cytopenia. During a median follow up period of 41.7 months (range 0.5-260.7), 24/58 (41%) experienced acute graft-versus-host disease (GVHD) and 33/49 (67%) evaluable patients developed chronic GVHD. Graft failure was seen in 2 patients - one primary and the other secondary. MF relapse was seen in 13/58 (22%) after a median time of 1.1 years post-AlloHSCT (IQR 0.7-2.4). The transplant-related mortality (TRM) was 25% at 1 year and 28% at 3 years post-AlloHSCT. The most common causes of death were infection (7 patients), disease relapse (6 patients), and multiorgan failure (5 patients). Transfusion independence was achieved in 45/58 (78%) patients by day +100 and in 40/44 (90%) by 1-year post-AlloHSCT. 17/48 (35%) evaluable patients had persistent grade 3 fibrosis on their day+100 bone marrow biopsy. The estimated 1-year, 5-year and 10-year RFS rates were 66% (95% CI 52-76), 55% (95% CI 41-67) and 47% (95% CI 42-61) respectively. The estimated 1-year, 5-year and 10-year OS rates were 72% (95% CI 59-82), 63% (95% CI 49-74) and 54% (95% CI 37-68) respectively. There were no differences in RFS (p=0.40) and OS (p=0.23) between those who received ruxolitinib pre-transplant vs. those who did not. Conclusion In our cohort, approximately half the AlloHSCT recipients achieved long-term survival, many in remission (10-year OS 54%; 10-year RFS 47%). TRM was seen in 25% within the first year after AlloHSCT, with patients most commonly succumbing to infections. The graft failure rate was low at 3%. An increasing number of patients received pre-AlloHSCT ruxolitinib in the recent years but we were unable to demonstrate improved transplant outcomes with its use in this single centre cohort.

Safety and Efficacy of Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host-Disease

Introduction Graft-versus-host disease(GVHD) is a severe complication of allogeneic hematopoietic cell transplantation(alloHCT), directly linked to increased morbidity and mortality. Despite novel biologic agents under study or commercial use in this field, corticosteroids and conventional intensified immunosuppressive therapy remain the cornerstone of treatment. Extracorporeal photopheresis (ECP) has been used as an alternative treatment. We studied the safety and efficacy of ECP in a large real-world cohort of GVHD patients. Methods We enrolled consecutive patients, of our JACIE-accredited center, that received ECP post alloHCT over the last 2 decades for cGVHD and over the last decade for steroid-dependent or refractory grade II-IV aGVHD. All patients with unrelated or haploidentical donors received thymoglobulin (ATG) 5mg/kg as prophylaxis. GVHD prophylaxis included cyclosporine-methotrexate in myeloablative and cyclosporine-MMF in reduced toxicity/intensity regimens. Before ruxolitinib or ibrutinib availability, MMF, cyclosporine or ATG were commenced as second line treatment in steroid-refractory patients, depending on previous prophylaxis. ECP was mostly administered as third line treatment for cGVHD and after assessment of response of 5 days of steroid treatment according to our protocol: 1 session/week for the 1 st month for cGVHD and 2sessions/week for aGVHD, 1 session/2 weeks for 3 months, evaluation of response and 1 session/month for 6 months. Before Ruxolitinib's availability, ATG was commenced simultaneously with ECP initiation in steroid-refractory aGVHD patients. Results We studied 112 patients with moderate or severe cGVHD. Only 13 received 4 or less ECP sessions because of severe GVHD-related morbidity and were excluded from further analysis. Median ECP sessions were 17(6-49). There were no ECP-related adverse events. 67 patients presented with cutaneous sclerosis manifestations, 73 mucocutaneous disease, 36 liver, 42 visceral and 27 lung involvement. ECP was commenced as second line in 35 patients. Ruxolitinib was administered in combination with ECP in 19 patients, while ibrutinib in 2. Bacterial infections were observed in 43 patients, viral in 38 and fungal in 11 patients. Only 19 patients did not show response. Significantly lower rates of response presented in patients with visceral involvement(p=0.037) and earlier post-transplant GVHD diagnosis (p=0.001). With a follow-up of 45.2 (5.6-345.1) months, 5-year CI of cGVHD-related mortality was 21.2% and was significantly reduced in patients with ECP response (p&amp;lt;0.001). 5-year OS was 65.3% and was independently associated with HLA matching (p=0.011), higher number of ECP sessions(p&amp;lt;0.001), later initiation of ECP (p=0.002), response to ECP (p=0.036) and no relapse(p=0.001). Regarding aGVHD, we studied 28 patients, aged 45 (18-67), with myeloablative (16), reduced toxicity (8) and intensity (4) conditioning, from sibling (4), matched (11) or one locus mismatched (12) volunteer unrelated and haploidentical (1) donors. Disease risk index was very high (1), high (11), intermediate (14) and low (2). aGVHD was observed at day +17(8-50). Skin, intestine and liver involvement was evident in 9 patients, skin and intestine in 13 and skin only in 6 patients. 13 patients were steroid-dependent and 15 steroid-refractory. ECP was commenced at day +18 (8-56) for 15 (4-20) sessions. The majority of patients (19/27) presented partial (7), very good (11) or complete (1) response. With 9.9 (1.7-113) months of follow-up, immunosuppression was reduced in 12/27 and ceased in 1 patient. Clinically significant bacterial infections were found in 19 patients, fungal in 3, CMV and EBV reactivation in 19 and 12 respectively and other viral in 6 patients. Cumulative incidence of aGVHD was 56.4 at 1-year.Five-year overall survival (OS) was 34%. Reduction of immunosuppression(p=0.026) and number of ECP sessions(p&amp;lt;0.001) were associated with improved OS, irrespectively of other factors. In particular, optimal OS was observed in patients that received more than 19 ECP sessions (Figure). Conclusion Our data confirm that ECP is safe and effective for GVHD. Even in the era of novel biologics, ECP should be considered early in the course of GVHD, before irreversible end organ damage has been established. Combination with other treatments and individualized treatment algorithms remain important unanswered questions.

Clinical impact of cryopreservation of allogeneic hematopoietic cell grafts during the onset of the COVID-19 pandemic

AbstractAt the onset of the COVID-19 pandemic, the National Marrow Donor Program mandated the cryopreservation of hematopoietic cell grafts from volunteer unrelated donors because of numerous patient and donor safety concerns and logistical hurdles. Using the Center for International Blood and Marrow Transplant Research outcomes database, we report the impact of cryopreservation on overall survival (OS) and other outcomes within 1 year after hematopoietic cell transplantation (HCT). We analyzed 1543 recipients of cryopreserved allografts receiving HCT at US centers during the first 6 months of the pandemic and compared them with 2499 recipients of fresh allografts during a 6-month period in 2019. On multivariable regression analysis, we observed no difference in the OS (P = .09), nonrelapse mortality (P = .89), graft-versus-host disease (GVHD), or GVHD- and relapse-free survival (P = .58) in recipients of cryopreserved vs fresh allografts. Disease-free survival (DFS) was lower in the cryopreserved allograft recipients (P = .006) because of a higher risk of relapse (P = .01) compared with the fresh allograft recipients. Primary graft failure was higher (P = .01), and the risk of chronic GVHD was lower (P = .001) with cryopreservation compared with fresh grafts. In conclusion, although there was no negative impact of cryopreservation on OS, relapse was higher, and DFS was lower than that with no cryopreservation. Fresh grafts are recommended as the pandemic-related logistical hurdles resolve. Cryopreservation should be considered an option for patients when fresh grafts are not feasible.

Supporting family members requested to donate hematopoietic stem cells to a relative: development and pilot testing of a psycho-educational resource

Abstract Background: In light of the increased demand for related donors in allogeneic stem cell transplantation, recognition of the psychosocial issues has also emerged. While resources supporting unrelated volunteer donors exist, none address the emotional issues specific to being a related donor. Providing related donors with preparatory information could help improve the overall donation experience and donor's outcomes. Objective: The objectives of this study were to develop and pilot test a print-based psycho-educational resource to support donors in coping with the physical and emotional aspects of donating to a relative. This article describes the development and pilot testing of the resource. Methods: Seventeen related donors and eight transplant nurses and physicians (transplant professionals) completed a survey and provided quantitative and qualitative feedback on the acceptability of the resource and preferences regarding the ideal distribution time. Results: Respondents endorsed the resource and found it useful and appropriate for the information needs at different stages of the donation and transplant process. The most useful reported components of the resource were testimonials from previous donors and explanations of blood cancers and the stem cell donation process. Most donor respondents indicated that the resource should be distributed as soon as possible while transplant professionals felt this should be after tissue typing, once the donor is confirmed as suitable. Respondents requested additional information on the side effects of donating and the possibility of being asked to repeat donation if the recipient relapses. More donor testimonials were also desired. Conclusion: The resource appears to be acceptable to donors and transplant professionals and helpful for developing confidence about coping with the physical and emotional aspects of donation. Findings from this study are currently being used to further refine and deliver the resource in additional formats.

Allogeneic bone marrow transplantation for aplastic anemia.

After more than 60years of intense research in allogeneic hematopoietic cell transplantation (HCT), this therapy has progressed from one that was fraught with seemingly insurmountable complications to a standard treatment of patients with aplastic anemia. During the 1970s and 1980s, HCT donors were almost exclusively HLA-identical siblings. Subsequent advances in the understanding of the complexity of the HLA region along with the development of molecular HLA typing and the establishment of unrelated volunteer donor registries have resulted in an ever-increasing use of such donors. Most recent breakthroughs have enabled HLA-haploidentical HCT and, thereby, finding donors for nearly every patient. The outstanding outcomes reported with any of the donor options have made allogeneic HCT the preferred treatment over immunosuppressive therapy.

241.6: Hematopoietic Cell Transplantation From Volunteer Unrelated Donor Between 2016 and 2021: A Collaborative Study GATMO-TC and INCUCAI

241.6: Hematopoietic Cell Transplantation From Volunteer Unrelated Donor Between 2016 and 2021: A Collaborative Study GATMO-TC and INCUCAI

EVALUATION OF THE AWARENESS OF STEM CELL DONATION

Objective: Many diseases, including bone marrow cancers (ALL, AML, etc.), lymphomas, hereditary anemia, and immune deficiencies, can be treated with hematopoietic stem cell transplantation (HSCT). Donors with HLA match are first sought from the patient’s siblings, parents, and close relatives. If a suitable donor cannot be found within the family, the search for unrelated volunteer donors begins. HSC banks were created in order to pool volunteer donors. More than 40 million stem cell donors and 136 banks affiliated and collaborate with the World Association of Donor Banks (WMDA). These banks seek to find the most suitable stem cell donor for the patient by collecting tissue groups from the pool of donors and comparing them to tissue groups from patients who applied completely voluntarily. The purpose of this study is to determine the knowledge and attitudes toward stem cell donation of 5th year students at the Istanbul Faculty of Medicine and randomly selected adult members of society. Material and Methods: The study included 285 students and 168 adults. Both groups completed a questionnaire with 21 questions using the interview under observation method. Results: In a statistical comparison of student and public participants in terms of stem cell donation, the student group was found to be far more aware than the public participant group. When compared to the public participant group, the student group’s desire to be stem cell donors was found to be very significant. The school in the student group and the written/visual media in the public participant group were extremely important in raising awareness. Conclusion: The survey study we conducted revealed that the knowledge level of the public was insufficient, and the knowledge level of medical students was deficient. Information about stem cell donation should be disseminated in the written/visual media, in health institutions, and during the education period, in order to raise societal awareness and increase the number of donors in comparison to the country’s population.

Human leukocyte antigen allele and haplotype frequencies in Singapore bone marrow donors and cord blood units.

We describe the allele and haplotype frequencies seen in a volunteer unrelated bone marrow donor registry, a public cord blood bank, and donor/recipient samples processed by the Health Sciences Authority (HSA) in Singapore. Historical human leukocyte antigen (HLA) typing reports were anonymized and combined. They were checked for HLA typing nomenclature discrepancies or ambiguities using the HLA-net UNIFORMATE tool, and for analysis, the validated data were subsequently separated into Chinese, Malay, Indian, and "Others," according to the race classification system used in Singapore. Individual ethnic allele and haplotype frequencies were calculated with the HLA-net GENE[RATE] pipeline using basic statistics. The Basic Statistics Tool of HLA-net was used to estimate haplotype frequency using an expectation maximization algorithm, given a set of multi-allelic data pairs for a given HLA locus. The outputs downloaded from the site comprised plain text files with haplotype frequency estimates, results of a global linkage disequilibrium test, and standardized residuals (stdres) corresponding to deviations from expected frequencies. HLA typing results from 59,186 individuals met the inclusion criteria, yielding 118,372 analyzable alleles. In our study population, the haplotype A*33:03-B*58:01-C*03:02-DRB1*03:01～DQB1*02:01:01G with a frequency of 4.91% was the most common. This haplotype was also the most common among Singaporean Chinese donors. Consistent with the predominant Chinese population, haplotypes with a frequency greater than 1% were also the most frequently observed haplotypes in the Singaporean population. In the Malay donor population, the most common haplotype was A*33:03～B*44:03～C*07:01:01G～ DRB1*07:01-DQB1*02:01:01G, with a frequency of 3.41%, whereas within the Indian donor population, the most common haplotype was A*01:01-B*57:01-C*06:02～DRB1*07:01-DQB1*03:03, with a frequency of 3.42%. Haplotype diversity and composition statistics within donor pools provide HLA background data required for the targeted recruitment of donors to support the hematopoietic stem cell donor requirements of the country. These data may be used in the future to devise donor recruitment strategies for optimizing the donor pool through targeted publicity and accruals.

Early Cytomegalovirus Reactivation after Allogenic Bone Marrow Transplantation Is Associated with the Loss of Recipient-Derived Humoral Immunity and Is Reduced By IL-6 Inhibition

Background:Interleukin-6 (IL-6) promotes the differentiation of pathogenic T cells and represents a dominant pathway of cytokine-dysregulation and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) reactivation is a common and life-threatening infectious complication following allogenic bone marrow transplantation (BMT). The role of T cell immunity is long-established, and our group recently demonstrated that CMV strain-specific immunoglobulins (Ig) are critical in preventing CMV reactivation in preclinical models (Martins JP et al, Science 2019).Methods and Results:In a phase I/II clinical trial (Kennedy GA et al, Lancet Onc. 2014), we observed unexpectedly low rates of CMV reactivation following IL-6 receptor (IL-6R) blockade with tocilizumab (TCZ) compared to historical control (8/35 vs 20/43, P < 0.05). We used our preclinical models of murine CMV (MCMV) reactivation to pursue the mechanisms. We transplanted bone marrow (BM) and T cells from naïve B6 donors into CMV-latently infected B6D2F1 recipients and monitored MCMV reactivation. Ablation of IL-6R in donor T cells (using B6 CD4 cre x IL-6R fl/fl transgenic mice; IL-6R -/-) significantly reduced MCMV reactivation 5 weeks after BMT, as measured by plasma viremia and infectious viral loads in the liver (Fig 1A).Next, we examined the contribution of donor T and B cells to the suppression of MCMV reactivation by IL-6R inhibition. At 2 - 3 weeks after BMT and prior to MCMV reactivation, cytokine (IFNɣ/TNF) secretion from CD4 + T cells (in response to MCMV infected DC) was not detectable; MCMV m38 tetramer + CD8 T cells were present at very low frequencies (< 0.1% of CD8 T cells) which were not altered by IL-6R ablation. The frequency of CXCR-5 +PD-1 + T FH cells was comparable or lower in IL-6R -/- vs wild-type (WT) T cells after BMT. Transplant of BM from B6.μMT mice (unable to generate mature B cells and plasma cells) did not increase MCMV viremia (Fig 1B), excluding a role for donor B cells. Thus, early MCMV reactivation in the presence of IL-6 is independent of MCMV-specific T cells and donor B cells.To study the effects of IL-6 on recipient-derived humoral immunity we quantified MCMV-specific IgG in plasma after BMT and found that levels were significantly higher in recipients of IL-6R -/- T cells (Fig 1C). Furthermore, MCMV-IgG levels in plasma correlated with MCMV viremia (r = - 0.72, P < 0.0001) and viral loads in liver (r = - 0.68, P < 0.0001). MCMV-IgG2a, which can only be generated by B6D2F1 recipients, was significantly higher in recipients of IL-6R -/- T cells, confirming that differences in humoral responses were of recipient-origin. To define relevant mechanisms, we examined the kinetics of IgG after BMT by monitoring the loss of murine IgG (transferred on day 0) in plasma (Fig 1D). Recipients of IL-6R -/- T cells showed significantly slower loss of IgG than recipients of WT T cells, with or without GVHD prophylaxis with cyclosporine (CSA). Thus, ablation of IL-6 signaling in donor T cells is associated with reduced loss of recipient IgG and protection from MCMV reactivation, an outcome which seems independent of the effects of IL-6 on GVHD.We correlated our findings with data from a recent randomized, placebo-controlled, double-blind phase III clinical trial of TCZ administration on Day -1 of BMT (Kennedy GA et al, Blood 2021). TCZ reduced CMV reactivation in at risk seropositive BMT recipients of volunteer unrelated donor grafts regardless of acute GVHD (all at risk recipients, TCZ vs. control: 12/26 vs 21/28, P = 0.03; at risk without grade 2-4 GVHD, TCZ vs control: 6/18 vs 9/13, P = 0.03). TCZ did not alter the frequency of B cells or the frequency and function of HCMV-specific CD8 + T cells, quantified by HCMV-pMHC tetramer-staining and HCMV peptide-specific cytokine (IFNγ/TNF) secretion. In contrast, levels of HCMV-specific IgG at day +30 in HCMV-seropositive recipients were significantly higher in the TCZ versus control group (Fig 1E). Consistent with our preclinical studies, the level of HCMV-IgG significantly and inversely correlated with early HCMV reactivation (within 35 days) after transplant.Conclusion:These data confirm the importance of recipient-derived humoral immunity in controlling early CMV reactivation in clinical BMT recipients. Critically, we demonstrate the ability of IL-6R blockade to maintain protective humoral responses until effective donor-derived adaptive immunity can be generated. [Display omitted] DisclosuresBoeckh: Merck: Consultancy, Research Funding; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; GSK: Consultancy. Hill: Generon corporation: Consultancy; NapaJun Pharma: Consultancy; Compass Therapeutics: Research Funding; Syndax Pharmaceuticals: Research Funding; Applied Molecular Transport: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Roche: Research Funding; Neoleukin Therapeutics: Consultancy.

Is Haploidentical Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide Feasible in Sub-Saharan Africa?

Identifying a suitable volunteer unrelated donor (UD) in South Africa is challenging due to the highly diverse ethnic groups and mixed-race populations in this region. Haploidentical hematopoietic cell transplantation (haploHCT) is thus an attractive procedure for patients with high-risk hematologic malignancies. This study was conducted to assess the safety and feasibility of haploHCT in South Africa. We retrospectively analyzed the outcome of 134 patients with hematologic malignancies who received unmanipulated haploHCT with post-transplantation cyclophosphamide at 2 high-volume HCT centers between 2014 and 2019. We assessed overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse incidence (RI), and incidence of acute GVHD. The median recipient age was 44 years (range, 15 to 73 years) and the median donor age was 36 years (range, 9 to 68 years). Acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) and acute lymphoblastic leukemia (ALL) were the most common indications for haploHCT (61.2%). The European Society for Blood and Marrow Transplantation risk score was ≥5 in 44 patients (32.8%). Seventy-seven patients (57.4%) received a myeloablative conditioning regimen. The majority of patients received a sex-matched transplant (57.4%) and had peripheral blood stem cells (PBSCs) as the stem cell source (70.9%). Sixteen patients (11.9%) had an incongruent cytomegalovirus serostatus at transplantation. The median duration of follow-up was 10.8 months (range, 0.36 to 70.8 months). OS was 56% (95% confidence interval [CI], 47% to 64%) at 1 year and 37% (95% CI, 28% to 47%) at 3 years. DFS was 47% (95% CI, 38% to 55%) at 1 year and 32% (95% CI, 24% to 41%) at 3 years. The 100-day and 3-year cumulative incidence of NRM was 18% (95% CI, 11% to 25%) and 41% (95% CI, 32% to 50%), respectively, and the 1- and 3-year cumulative RI was 16% (95% CI, 11% to 24%) and 21% (95% CI, 14% to 29%), respectively. The 1-year OS was 55% (95% CI, 40% to 67%) for the patients with AML/MDS versus 41% (95% CI, 21% to 60%) for those with ALL. Forty-five patients (41.7%) developed acute GVHD by day +100; of these, 80% had grade I-II disease. Fifty patients (37.5%) developed cytomegalovirus infection that required therapy. On multivariable analysis, older donor age was an independent risk factor for lower DFS. RI was higher for diagnoses other than acute leukemia/MDS (relative risk [RR], 2.62; 95% CI, 1.12 to 6.15; P=.027), decreased for PBSC versus bone marrow (RR, 0.43; 95% CI, 0.19 to 0.95; P=.038) and decreased for offspring donors (RR, 0.25; 95% CI, 0.09 to 0.67; P=.006). These data support the feasibility of haploHCT and suggest that unmanipulated haploHCT using a younger parent or offspring donor is a viable option for adults in sub-Saharan Africa with acute leukemia and MDS who lack a suitable related or unrelated donor.

Determinants of Long-Term Survival Following Allogeneic Stem Cell Transplantation for Multiple Myeloma: A Multi-Centre Analysis Across the United Kingdom and Australia

IntroductionDespite the accepted utility of autologous stem cell transplantation for multiple myeloma, the role of allogeneic stem cell transplantation (alloSCT) remains controversial (Dhakal et al., 2016). The differences in practices across centres in patient selection, conditioning regimens and post-transplant care clouds the comparison of available studies. Moreover, the high rates of non-relapse mortality despite disease eradication demand an understanding of pre-allograft determinants of long-term survival. Included within these determinants is the appropriate timing for alloSCT, an important variable given the growing list of available myeloma therapies. We sought to identify the variables, including the influence of transplant centre and timing that govern long term survival following alloSCT for myeloma within integrated data in a large group of patients across three centres.MethodsA retrospective analysis of 93 patients undergoing alloSCT for multiple myeloma between January 2000 and June 2017 at three tertiary transplant centres - the Royal Melbourne Hospital, Australia and The Christie and Central Manchester NHS Foundation Trusts, United Kingdom. We collected: demographic data; disease-specific data, including previous treatment, disease status prior to alloSCT, and time from autologous SCT to alloSCT; and peri-transplant data including donor source and gender, stem cell dose, conditioning regime, and donor and recipient cytomegalovirus serological status. We measured overall survival, cause of death, acute and chronic graft versus host disease and progression free survival. Log-rank testing and cox regression analysis was performed with a multivariate regression model established on the basis of significant univariate associations.ResultsMedian age for the 93 patients at transplant was 49 years old (range 28 to 66 years). 65% of patients were male (n=60). 51 patients underwent alloSCT at the Royal Melbourne Hospital, 18 and 24 patients at the Christie and Central Manchester NHS Foundation Trusts, respectively. Patients received a median number of 2 lines of treatments prior to alloSCT (range 0-6). 51% (n=47) patients received stem cells from voluntary unrelated donors (VUD), and 49% from siblings (n=46). 78% (n=72) received a reduced intensity conditioning consisting of either 25mg/m2 fludarabine, 60mg/kg cyclophosphamide or 30mg/m2 fludarabine with 2Gy total body irradiation; 20% (n=18) received non-myeloablative conditioning with 30mg/m2 fludarabine and 750mg/m2 cyclophosphamide, 2% (n=3) underwent myeloablative conditioning with 60mg/kg cyclophosphamide and 4Gy total body irradiation.Median overall survival (OS) for the whole group was 8.1 years (interquartile range = 1.3 to 12.7 years). No difference was observed in OS across the three centres (log rank p=0.84) or across country (log-rank p=0.56). Conditioning regimens containing total body irradiation showed no association with relapse post allo SCT (odds ratio 0.68, 95% CI 0.30-1.55) and did not affect OS (hazard ratio, HR =1.00, 95% CI = 0.51-2.00).In accordance with previous findings (Dhakal et al., 2016), age over 40 at alloSCT was associated with a poorer survival (HR = 2.47, 95%CI 1.20 to 5.09). Patients who had stable or progressive disease at allograft showed poorer OS, even when controlling for number of lines of therapy and previous relapse (HR = 3.03, 95% CI 1.31-6.97).Patients who underwent alloSCT over one year following autologous SCT showed 3.4 times increased risk of death (95% CI 1.52-7.09) and 2.16 times increased risk of relapse (95% CI 1.18-3.93) even when controlling for age, prior relapse history, number of lines of treatment, disease status prior to alloSCT and transplanting hospital (Figure 1).ConclusionThis large multi-centre multivariate analysis demonstrates that transplant centre and low dose total body irradiation does not influence OS following alloSCT for multiple myeloma. Importantly, the time between autologous SCT and alloSCT of greater than one year is a strong predictor of poor OS. This remains true when controlling for several established risk factors. Our results demonstrate the importance of patient selection and timing in order to maximise OS for patients undergoing alloSCT for multiple myeloma.ReferenceDhakal B, et al. 2016. Allogeneic stem cell transplantation for multiple myeloma: is there a future? Bone Marrow Transplant, 51, 492-500. [Display omitted] DisclosuresRoutledge:Gilead: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Harrison:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavet:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Speaker, Research Funding. Tholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Ritchie:Amgen Inc.: Honoraria.

Hospital in the Home Delivery of Conditioning Therapy for Allogeneic Haematopoietic Stem Cell Transplantation: A Novel Single Centre Patient Focused Approach

Introduction: High dose therapy with Allogeneic Haematopoietic Stem Cell Transplantation (AlloHSCT) has traditionally been performed as an inpatient procedure. However, with improvements in supportive care and patient selection it is possible to safely deliver conditioning chemotherapy in an outpatient setting (Subirà M et al., 2003). While deemed an “outpatient procedure” this method is currently delivered on large day units which requires the patient to attend daily, often only spending the night at home.To reduce these daily visits The Royal Melbourne Hospital (RMH) Bone Marrow Transplant department in collaboration with the Hospital in the Home (HIH) department developed an innovative program to safely deliver Fludarabine chemotherapy as part of conditioning for AlloHSCT in the patient's home. This process involved a daily patient review by a HIH Doctor as well as twice daily visits by a HIH nurse to administer chemotherapy and supportive care in the comfort of the patient's home. Here we report on the safety outcomes of HIH AlloHSCT vs inpatient (IP) care, specifically complications and outcomes.Methods: A retrospective case note audit identified 395 consecutive AlloHSCT patients who received Fludarabine based conditioning between 2011 and 2017 at the RMH. Of these 130 received Fludarabine as part of the HIH Program and 265 as a traditional IP.Results: Of those treated as HIH patients, median age was 51 years (range 18-69). 59% patients were male (n=77) and 41% Female (n=53). Underlying disease groups included Leukaemia (n=53; 40%), Lymphoma (n=35; 27%), Myelodysplatic/Myeloproliferative (n=28; 21%), Myeloma (n=11; 9%) and Non-malignant (n=3; 3%). 2% of patients had myeloablative conditioning (n=2) and 98% received Reduced Intensity Conditioning (n=128). 57% (n=73) received stem cells from a sibling (Sib), 41% (n=54) from Voluntary Unrelated Donors (VUD) and 2% (n=3) from Umbilical Cord Donors.Median total Length of Stay (LOS) for HIH patients was 27 days (Range 10-97) with a median of 5 days (range 2-8) at home as part of this. The LOS for those receiving fludarabine as an IP was not significantly different at 26 days (range 5-174; p=0.209). Total number of IP Bed days saved through the HIH program was 682. There was no significant difference in median time to neutrophil engraftment (HIH 20 vs IP 17 days; p =0.95) or platelet engraftment (HIH 23 vs IP 20 days; p=0.99). Having chemotherapy as a HIH patient had no effect on outcome (HR 1.01). There is no difference in Overall Survival (OS) between the two groups (HIH 17 vs IP 16 months - see Figure 1) while Median OS was not reached.Of the 130 patients who were treated in the HIH Program only 11 had an unplanned admission before Day 0 of their AlloHSCT. Reasons for readmission included suspected infection (n=8; only one culture positive), vasovagal (n=1) and anxiety (n=2). Of note, four of these admissions arose in the first three months of the program with the other seven readmissions occurring over the following six years, with a readmission rate of approximately 5% (7/126 patients).Conclusion: The HIH delivery of chemotherapy and supportive care as part of conditioning for AlloHSCT in the patient's home is both safe and effective. It resulted in a median of five bed days saved per patient (Total number of bed days saved = 682), allowing the department to increase bed capacity without the costs associated with building a new ward. Additionally, the risk of complications was low (approximately 5%) and those that did occur were safely managed.Figure 1 - Comparison of Survival Between HIH and IP AlloHSCT Patients [Display omitted] DisclosuresRoutledge:Celgene: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria. Ritchie:Amgen Inc.: Honoraria.

Revisit of Optimal Donor Number Estimation in the Hong Kong Bone Marrow Donor Registry.

High resolution typing of the HLA-DPB1 locus for patient who requested for hematopoietic stem cell transplantation (HSCT) workup has recently become mandatory by the National Marrow Donor Program (NMDP) in order to facilitate matching between donors and recipients for better outcomes. The likelihood of identifying HLA matched donors in Hong Kong, on top of the existing HLA-A, -B, -C, and -DRB1 loci, is revisited in this study. HLA-A, -B, -C, -DRB1 and -DPB1 genotypes of 5,266 volunteer unrelated Chinese donors from the Hong Kong Bone Marrow Donor Registry (HKBMDR), were included in this study. Matching models were employed to determine the matching probabilities for 10/10(DPB1) and 9/10(DPB1) HLA match. The matching probabilities are 20% at 10/10(DPB1) HLA match and 55% at 9/10(DPB1) match, based on the existing 130,000 donors in the HKBMDR. The likelihoods of match become 27% and 65% respectively, by increasing the registry to 250,000. However, if DPB T-cell-epitope (TCE) model is considered in the matching, the probability will increase to 46% at 10/10 DPB1 permissive mismatching. Our findings provide vital information about the future planning on the targeted recruitment size, HLA typing and search strategies of the donor registry and arose the transplant physicians’ acceptability to 9/10(DBP1) or 10/10(DBP1) HLA match. Nevertheless, the marrow donor registry has planned for increasing the registry size and bringing down the age of recruited donors which will ultimately enhance patient outcome.

A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day −1. All patients received T-cell–replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis

AbstractPatients with Ph+ chronic myelogenous leukemia who relapse after a first allogeneic stem cell transplant still have a possibility of long-term survival. To assess the value of the individual therapeutic options, the factors predicting outcome should be identified. We investigated data from 500 patients who relapsed before July 1996; follow-up was updated during 1998. The actuarial survival from relapse was 34.2% (95% confidence interval [CI]: 29.9%-38.5%) at 5 years and 23.4% (95% CI: 18.9%-27.9%) at 10 years. Survival after relapse was significantly related to 5 factors: time from diagnosis to transplant (< 2 years vs ≥ 2 years), disease phase at transplant (first chronic phase vs other), disease stage at relapse (cytogenetic or chronic phase vs advanced phase), time from transplant to relapse (< 1 year vs ≥ 1 year), and donor type (HLA-identical sibling vs volunteer unrelated donor). The effects of individual adverse risk factors were cumulative: The probability of survival at 10 years decreased stepwise from 42% (0 factors), 32% (1 factor), 14% (2 factors), 3% (3 factors), to 0% (4 or 5 factors). Novel strategies for high-risk patients are warranted. We conclude that these 5 factors should be taken into account when comparing results of salvage therapies in patients with Ph+ chronic myeloid leukemia relapsing after allogeneic stem cell transplant.

Global exchange of Cord Blood Units in 2018

Background & Aim A key project of the World Marrow Donor Association (WMDA) is the annual global trends report, which has become an established instrument to describe the current status of haematopoietic stem cell (HSC) donation worldwide. The report is used to observe trends and changes in number and stem cell source of HSC donations as well as the global exchange of these products. Methods, Results & Conclusion Methods: Organisations worldwide are asked to report data on the number of unrelated volunteer donors and cord blood products listed in their database, as well as the number and cell source of HSC donations provided and to which countries. The data collection has been done through an online questionnaire and the data is automatically stored in an online database. Quality control measures include data validation checks within the reporting system as well as manual data checks done by the WMDA staff. For this abstract we have looked specifically at the global exchange of cord blood units (CBUs) in 2018 compared to 2012. The last year we saw an increase in the shipments of CBUs globally was 2012, which is why we choose to compare to 2012. Additionally, we have calculated the 2018 CBU shipping rates relative to the number of CBUs available. The number of national shipments is included in these shipping rates. Results In 2018, 2.783 CBUs were shipped globally; 419 (15%) were shipped outside of the country of origin and 2.364 (85%) CBUs were shipped nationally (graph 1). In 2012, 4.150 CBUs were shipped globally; 870 (21%) were exported and 3.280 (79%) CBUs were shipped nationally (graph 2). In the past six years, WMDA has observed a 33% (1.376 CBUs) decrease in total shipments, 52% (451 CBUs) in exported shipments and 28% (916 CBUs) decrease in national shipments. The decrease was observed on all continents except Asia. The top 10 shipping rates for CBUs were seen in Japan, UK, China, USA, France, Canada, Spain and Singapore (table 1). Over 95% of the globally used CBUs are provided by these 10 countries. Over 13 countries have a cord blood bank operational and provided less than 5 CBUs and 9 countries did not ship any CBU in 2018. Conclusions The past six years, the WMDA has observed a dropdown in the use of CBUs on a global level. While there is a global decrease in the use of the CBUs, this trend is not observed in Asia. The global CBUs provision is facilitated by a small number of countries.

Common, intermediate and well-documented HLA alleles in world populations: CIWD version 3.0.0.

A catalog of common, intermediate and well‐documented (CIWD) HLA‐A, ‐B, ‐C, ‐DRB1, ‐DRB3, ‐DRB4, ‐DRB5, ‐DQB1 and ‐DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two‐field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well‐documented (≥5 occurrences) or not‐CIWD. Overall 26% of alleles in IPD‐IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two‐field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well‐documented alleles. Full‐field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.

Prospective Evaluation of Alternative Donor from Unrelated Volunteer Donor and Cord Blood in Adult Acute Leukemia and Myelodysplastic Syndrome: No Difference between Unrelated Donor and Cord Blood

Prospective Evaluation of Alternative Donor from Unrelated Volunteer Donor and Cord Blood in Adult Acute Leukemia and Myelodysplastic Syndrome: No Difference between Unrelated Donor and Cord Blood