Initial Allogeneic Transplantation Research Articles

Early Infection after Allogeneic Transplant Increases NRM without Influencing Relapse Rate

Intro: Relapse post allogeneic transplant is the leading cause of early mortality in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Known risk factors of relapse include persistent disease at the time of transplant, use of anti-thymocyte globulin, reduced intensity conditioning, and absence of chronic graft versus host disease (GVHD). Early infection has been reported to increase non-relapse mortality (NRM) while protecting against hematologic disease relapse (Auletta et al., Blood 2016). We sought to determine the influence of patient features and post-transplant early infection (bacterial, fungal, and viral) on acute GVHD, relapse, and mortality. Methods: Adult patients (N=146) with myeloid disorders (AML, MDS, MPN/CMML) who received an initial allogeneic transplantation from 2013-2018 at Oregon Health & Science University were retrospectively identified and followed until 6/30/20 for acquired infections, hematologic relapse, and survival outcomes. Time-to-event endpoints, starting from transplant date, were modeled with Cox regression for single events (overall survival [OS], cause-specific hazards for competing events) and Fine-Gray subdistribution regression for events with a competing risk (early infection vs. death, acute GVHD vs. death, relapse vs. NRM). Infection status (one or more confirmed infections) in the first 100 days post-transplant was considered as a time-dependent covariate. Results: Among 146 adult patients, 77% had AML, 54% were male, and the median age was 59 years (range 18 - 72). The Karnofsky score was 90-100 in 44% and 60-80 in 51% of patients. Using 2017 ELN risk guidelines for AML and IPSS-R for MDS and MDS/MPN, 11% of patients were classified as low risk, 33% as intermediate, and 50% as adverse. The median time from diagnosis to transplant was 5 months (range 2 - 203). At the time of transplant, 63% of patients had attained some degree of response (i.e., complete remission [CR] or hematologic improvement). However, 66% had minimal residual disease (defined as persistent cytogenetic abnormalities or leukemia-associated mutations detected by NGS). Fifty-one percent of patients had myeloablative conditioning and 90% received peripheral blood stem cell grafts with methotrexate and calcineurin-based GVHD prophylaxis. Donors were HLA-matched in 86% of patients, with haploidentical and umbilical cord blood grafts representing 10% and 3%, respectively. Forty-six percent of donors were positive for cytomegalovirus (CMV). Seventy-five percent (n=109) of patients had at least one infection in the first 100 days after transplant. Cumulative incidence rates of any infection are displayed in Table 1. The median time from transplant to first infection was 22 days, ranging from 0 to 73 days. Forty-three patients (29%) relapsed during study follow-up. The median time from transplant to relapse was 6.1 months (IQR 3.1 - 12.0). Over a median follow-up time of 18.7 months, 78 patients (53%) died, with median time to death of 4.1 months after transplant. Forty-six (59%) of the deaths were attributed to causes other than hematologic disease (i.e., infection, GVHD, other cancer). Low prognostic risk and total body irradiation during conditioning were associated with early infection (Table 2). In the multivariable setting, a higher rate of death was associated with male gender (HR=1.67; p=0.040), having at least a 6-month lag between diagnosis and transplant (HR=2.79; p<0.001), and contracting an infection of any type (HR=2.54; p=0.003; Table 3). There was no association between early infection and acute GVHD, which occurred in 85 patients (58.2%) with a median time to onset of 34 days. A greater incidence of acute GVHD was related to older recipient age (HR=1.88 for ≥50 years vs. <50; p=0.014), being male (HR=2.62; p<0.001), not having achieved a CR (HR=1.66; p=0.020), and undergoing transplant ≥ 6 months after diagnosis (HR=1.72; p=0.014). Infection did not correlate with the rate of relapse (HR=1.02, p=0.942) but significantly elevated the rate of NRM (HR=5.72, p<0.001). Time-independent variables associated with a higher probability of relapse were failure to attain a pre-transplant CR (HR=1.87; p=0.038) and having a CMV-positive donor (HR=2.11; p=0.016). Conclusion: Our retrospective study found that post-transplant early infection in AML and MDS/MPN patients did not impact relapse rate but drastically increased the rate of NRM. Disclosures Saultz: Kyn Theraputics: Research Funding. Maziarz:Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Novartis and Athersys: Other: DSMB participant; Novartis and Juno: Research Funding; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Athersys: Patents & Royalties.

Haploidentical Hematopoietic Stem Cell Transplantation with Treosulfan-Based Conditioning Regimen for Acute Leukemia Relapsing after Initial Allogeneic Transplantation

▪Background. Patients who experienced leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Strategies to prevent or overcome post-transplant disease recurrence are limited and their efficacy still remains unclear. Recently, HSCT using haploidentical T-replete source has found increasing feasibility and acceptance thanks to new transplant platforms (Luznik L. et al., Biol Blood Marrow Transplant, 2008; Peccatori J. et al., Leukemia, 2014), allowing lower rates of graft-versus-host disease (GvHD) and non-relapse mortality (NRM). We evaluated the outcome of haploidentical transplant approach performed as second transplant (HSCT2) for patients who suffered of acute leukemia (AL) relapse after a first allogeneic HSCT (HSCT1).Methods. We analyzed 42 consecutive patients (median age 48 years) who underwent HSCT2 from a haploidentical donor, different from the previous one, between 2007 and 2013 in our Institute. Patients suffered of acute myeloid leukemia (n=31), acute lymphoblastic leukemia (n=9) or biphenotypic AL (n=2) relapsing after HSCT1 (matched related: 21; unrelated: 17; mismatched related: 4; umbilical cord blood: 4). Thirty-seven patients (88%) received re-induction therapy before HSCT2: 13 of them achieved complete remission (CR), 16 did not respond and 8 patients were transplanted directly in aplasia. In 5 cases HSCT2 was performed without re-induction therapy, in active disease (AD). Median Hematopoietic Cell Transplant-Co-morbidity Index was 2 (range 0-6) at time of HSCT2.All patients received treosulfan (14 g/m2 for 3 days) and fludarabine (30 mg/m2 for 5 days) as part of preparative regimen for HSCT2; conditioning was intensified with total body irradiation (4 Gray) in 18 (43%) or with melphalan (70 mg/m2 for 2 days) in 6 patients (14%). GvHD prophylaxis consisted of mycophenolate mofetile and sirolimus combined with pre-transplant anty-thymocyte globuline (n=36) or with post-transplant cyclophosphamide (n=6). Unmanipulated peripheral blood stem cells were used as graft source in all cases.Results. Three out of 42 patients (7%) experienced early death in aplasia, while all the others achieved neutrophil engraftment (n=39, 93%), with no primary graft rejection. Complete remission of disease at day +30 was reached in 37 out of 39 evaluated cases (95%). Estimated overall survival (OS) and leukemia-free survival (LFS) (± SE) rates at 1 year from HSCT2 were 37% (± 8%) and 35% (± 7%), respectively (Figure 1A). One-year relapse incidence (± SE) amounted to 32% (± 7%) and NRM (± SE) to 31% (± 7%) (Figure 1A) (7 patients died for infectious, 5 for GvHD and 1 for central nervous system toxicity). Sixteen patients (38%) experienced of acute GvHD grade II-IV and 20 (47%) of chronic GvHD. Disease status at HSCT2 (AD vs CR) had no impact on OS (HR:1.26, 95% CI 0.58-2.76, p=0.564) and relapse (HR:1.35, CI 95% 0.46-3.76, p=0.61). Conversely, time of remission from HSCT1>6 months provided the better outcome in terms of estimated OS (±SE) at 1 year (50% ± 10%) compared to patients with shorter duration of remission (18% ± 9%) (HR:0.49, 95% CI 0.24-1.02, p=0.05) and reduced risk of relapse (HR:0.28, 95% CI 0.11-0.75, p=0.011) (Figure 1B). After a median follow-up time of 22 months (range 6-68), 11 patients (26%) were alive with sustained leukemia remission.Conclusions. These results demonstrate the feasibility of HSCT2 from a haploidentical donor as treatment for AL relapse after initial allogeneic transplant, showing rates of OS, LFS and NRM comparable to the reported in literature for HSCT2 from matched related or unrelated graft, using the same or different donor (Christopeit M. et al., J Clin Oncol, 2013). Interestingly, disease status at HSCT2 did not influence the outcome of transplant. While, in accordance with previous reports, duration of remission after HSCT1 is the major factor involved in predicting outcome of a second transplant due to an increased relapse incidence after HSCT2 in patients with shorter HSCT1 remission, reflecting diseases biologically different. If confirmed in a larger cohort, these data could be useful in decision making after HSCT1 failure for disease recurrence. [Display omitted] DisclosuresBonini:MolMed S.p.A.: Consultancy.

Prolonged Transportation Time Of Haemopoietic Progenitor Cells Does Not Impact Upon Engraftment Or Overall Survival Following Allogeneic Voluntary Unrelated Donor Transplantation

▪ IntroductionThe transportation of haemopoietic progenitor cells (HPC) from collection centre to transplant centre is a critical, but often overlooked process during allogeneic transplantation using voluntary unrelated donors (VUD). The policies of international donor registries support the rapid retrieval and infusion of HPC. However transplant centres are often challenged by transit times in excess of 24h when retrieving HPC from intercontinental collection centres. This single institutional retrospective study aimed to investigate if a prolonged transit time between collection and transplant centre impacted upon the rate of engraftment and overall survival of recipients of HPC collected from VUDs. MethodologyA retrospective analysis of outcomes following an initial allogeneic transplant performed at our institution between 1987 and 2013 was conducted using institutional databases. The time to neutrophil and platelet engraftment and overall survival was compared between recipients of VUD transplants with HPC retrieved from collection centres located overseas (transit time of > 24h) (n = 241; BM n = 50, PBPC n = 191), recipients of unrelated donor transplants with HPC retrieved from collection centres within Australia (transit time of <8h) (n = 334; BM n = 112, PBPC n = 222) and recipients of related HPC collected at the transplant centre (n = 807; BM n = 320, PBSC n = 487). All HPC retrieved from local and intercontinental VUD collection centres were transported in rigid coolers containing refrigerated gel packs prior to 2003 or isothermal cooling inserts post 2003. The temperature was monitored and maintained by the courier at between 2 and 8oC. ResultsThere was no significant difference in the days to neutrophil and platelet recovery (Table 1) between recipients of a VUD allogeneic transplant with HPC retrieved from a local collection centre compared with those recipients whose HPC was retrieved from an international collection centre. Retrieval and infusion of HPC from local collection centres is generally completed within 8h from collection whereas the interval from collection to infusion may vary between 24 to 90h when HPC are retrieved from intercontinental collection centres. Furthermore there was no significant difference in overall survival (Figure 1) of recipients of related donor allogeneic transplants performed without transportation of HPC and recipients of VUD allogeneic transplants whose HPC were retrieved from either a local collection centre or an intercontinental collection centre (Figure 1).Table 1Neutrophil and platelet engraftment post VUD allogeneic transplantationDays to Neutrophil Count of 0.5 x 109/L(median)Days to Platelet Count of 20 x 109/L(median)Unrelated BM (transit < 8h)1727Unrelated BM (transit > 24h)1726Unrelated PBPC (transit < 8h)1619Unrelated PBPC (transit > 24h)1619 [Display omitted] ConclusionOur study demonstrated no adverse effect on neutrophil and platelet recovery, or overall survival resulting from retrieval of HPC (BM and PBPC) from collection centres with transit times in excess of 24h and with some international retrievals requiring up to 90h transit times. A previous study had reported higher mortality rates and delayed platelet engraftment following HLA matched unrelated donor BM transplants facilitated by the National Marrow Donor Program with an interval of greater than 24h between collection and infusion (Lazarus et. al, Biol Blood Marrow Transplant 15: 589-596, 2009). At our centre HPC (BM and PBPC) are retrieved by trained couriers that monitor and maintain the temperature between 2 and 8oC. This is in contrast to NMDP recommendations that BM is transported at ambient temperature. Our data suggest that all HPC should be refrigerated to between 2 and 8oC and the temperature monitored during transportation. In addition, the courier should be trained to re-establish the optimal temperature for transportation if the temperature deviates from the recommended range. Disclosures:No relevant conflicts of interest to declare.

Confocal Imaging of Trans‐epithelial Trafficking by Immune and Umbilical Cord Stem Cells in the Neonatal Porcine Intestine

Maternal colostral leucocytes (CL) and peripheral blood mononuclear cells (PBMC) enter the neonatal circulation after ingestion in pigs and cattle. Porcine umbilical cord matrix stem cells (PUCs) are relatively non-immunogenic after initial allogeneic transplantation. Using intestinal explant cultures incubated with labelled cells and confocal microscopy, we demonstrated trans-epithelial trafficking of exogenous CL, PBMC and PUCs below the luminal surface after 72 h of culture. We orally administered PBMC and PUCs to pre-colostral neonatal pigs and tracked their location 8 or 24 h later. Both PBMC and PUCs were found in the intestinal wall of all samples. Exposure to 25% of acellular colostrum had no detected effect on trafficking. Labelled PUCs and PBMC were detected on the surface of the epithelium and in the lamina propria 8 h post-treatment and PBMC were also in the superficial submucosa. At 24 h, PUCs and PBMC were observed on the surface of the epithelium, in the lamina propria, superficial submucosa and deep submucosa. Our findings show the potential of PUCs for allogeneic engraftment in the neonatal intestine and may lead to cell-based delivery of therapeutics.

Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant

Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.

Outcome of Second Allogeneic Transplants Using Reduced Intensity Conditioning Following Relapse after an Initial Allogeneic Transplant.

The management of disease relapse following an allogeneic transplant is problematic. For patients with some diseases treatment with DLI alone can be successful. The use of a second allogeneic procedure has been associated with a prohibitively high TRM, especially when using myeloablative conditioning. Here we report the results of a British Society for Blood and Marrow Transplantation (BSBMT) registry retrospective multicentre analysis of 70 patients receiving a second allogeneic transplant using reduced intensity conditioning (RIC) after disease relapse following an initial allogeneic transplant. In 41 cases the first procedure was myeloablative and in 17 this was with RIC (unknown: 12). Over half of the first grafts were T cell depleted (TCD). The donor was an HLA identical sibling (48), unrelated (17) or other family member (2). In 11 cases a different donor was used at second transplant. The median age at first transplant was 39 (range: 8–69). The underlying diseases are as follows: AML 21, MDS 13, ALL 13, Lymphoma 11, CML 7, MPD 3, MM 2. For the second transplant, a variety of RIC regimens were used. Of these, 85% were fludarabine based and less than 20% include TCD. At the time of analysis, 27 patients were alive at a median follow-up of 1.7 years from second allograft (range: 0.3–7.4 years). In the cohort overall, the predicted overall survival and TRM at 2 years post second allograft were 27% and 27% respectively. Disease type was significantly associated with outcome (OS 1yr: lymphoma 82%, AML 32%, MDS 39%, ALL 41%, p=0.049). Age and disease status did not impact on OS or TRM. The median time to relapse after the first transplant was 1 year (range: 0.1–12.2). There was a significant survival advantage to those who relapsed more than a year post first allograft (2yr post second allograft: 33% vs 21%, p=0.038). In addition, patients with later relapses had a TRM of 12% at 2 years compared to 39% in those relapsing within a year (p=0.009). The incidence of acute GvHD was higher following the second procedure (43%) than the first (28%). Although aGvHD at any time did not impact on OS in the whole cohort, in those who relapsed prior to a year the presence of acute GvHD post second allograft was significantly associated with a superior outcome (p=0.001). The median time to relapse from the second transplant was 0.73 years (range = 0.1 – 1.6). The predicted relapse risk post second transplant was 52 % at 2 years. Those under the median age (p=0.029) and with acute leukaemia (1 yr post second transplant risk: AML 57%, MDS 34%, ALL 54%, lymphoma 14%; p=0.056) were at higher risk. Remission status prior to either transplant, acute or chronic GvHD post second allograft, donor type and time to first relapse did not impact significantly on relapse risk. In conclusion, compared to second myeloablative transplants, a second allograft using RIC can be performed with a low TRM in those relapsing more than one year after a first allograft, even when using UD. These patients achieved an encouraging OS of > 30% at 2 years. In those relapsing within a year of first transplant the development of GvHD was strongly associated with a better outcome.

Allogeneic Blood Stem Cell Transplantation for Refractory Leukemia and Lymphoma: Potential Advantage of Blood Over Marrow Allografts

Peripheral blood stem cells (PBSCs) have been used rarely for allogeneic transplantation because of concerns regarding graft failure and graft-versus-host disease (GVHD). We evaluated the results of allogeneic PBSC transplantation (allo-PBSCT) in 9 patients with refractory leukemia or lymphoma receiving myeloablative therapy followed by allo-PBSCT from an HLA-identical sibling donor. Three patients had relapsed 11 to 21 months after allogeneic bone marrow transplantation (allo-BMT) and underwent allo-PBSCT using the same donor. Six patients received PBSCs as their initial allogeneic transplant. Filgrastim-mobilized PBSCs were collected from the donors in 3 to 4 aphereses and cryopreserved. The apheresis collections contained a median nucleated cell count of 16.5 x 10(8)/kg (range, 10.8 to 28.7 x 10(8), 10.7 x 10(6) CD34+ cells/kg (range, 7.5 to 22.5 x 10(6)), and 300.0 x 10(6) CD3+ cells/kg (range, 127.8 to 1,523.2 x 10(6)). The median recovery of CD34+ progenitor cells after freezing, thawing, and washing was 106.4% (range, 36.7% to 132.0%). All patients received filgrastim posttransplant through engraftment, and cyclosporine and methylprednisolone were used for GVHD prophylaxis. Neutrophil recovery to greater than 0.5 x 10(9)/L and greater than 1.0 x 10(9)/L occurred at a median of 9 (range, 8 to 10) and 9 days (range, 8 to 11) posttransplant, respectively, which was similar to historical controls after allo-BMT and granulocyte colony-stimulating factor therapy. Platelets recovered to greater than 20 x 10(9)/L and greater than 50 x 10(9)/L at a median of 12 (range, 8 to 25) and 15 days (range, 11 to 59), respectively, which was significantly more rapid than for the controls (P < .01). Donor cell engraftment was documented by cytogenetics, fluorescence in situ hybridization, and/or restriction fragment length polymorphisms with longest follow-up of 283 + days. Three patients developed grade 2 acute GVHD involving only the skin. Three of five evaluable patients show limited chronic GVHD. Cryopreserved, filgrastim-stimulated allogeneic PBSCs may be a suitable alternative to allogeneic marrow for transplantation with the advantage of more rapid platelet recovery. Acute GVHD was minimal despite the infusion of 1 log more CD3 cells than with marrow allografts. Further studies are required to assess long-term risks of chronic GVHD.