Outcomes following second allogeneic stem cell transplant for graft failure or poor graft function: a single centre experience

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Kim, Moss A. Bruton Joe, Shanee Chung, Hannah Cherniawsky, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5321463/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Graft failure is a rare but life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). We aim to review the outcomes of patients who underwent a second allogeneic HSCT (HSCT2) for graft failure or poor graft function following a previous allogeneic HSCT (HSCT1) at our centre. This restrospectve study included adult patients receiving HSCT2 for graft failure or poor graft function between February 2001 and July 2021. Survival functions were estimated using the Kaplan-Meier method. Twenty-one patients were identified, 11 with primary and 10 with secondary graft failure. In the 14 patients for whom chimerism data was available, 10 had loss of donor chimerism, 2 had mixed chimerism, and 2 had full donor chimerism. The median time between HSCT1 and HSCT2 was 55 days (range 38-168 days) and 278 days (range 75-3074 days) for PGF and SGF, respectively. For HSCT2, matched unrelated donor was the most common donor type (33%) and the same donor as HSCT1 was used in 24%. Most patient received peripheral blood stem cell source (81%) and reduced intensity conditioning (100%) for HSCT2. Graft-versus-host-disease (GVHD) prophylaxis was calcineurin inhibitor-based with either methotrexate or mucophenolate mofetil. The median follow-up for survivors was 120 months (range 7-170). Overall survival was 52% at 2 years, and 46% at 5 years. Death before day+30 occurred in 5 patients (24%). Non-relapse mortality (NRM) was the major cause of treatment failure, with 2-year NRM of 48%. Infectious complications was the most common cause of death. Relapse occurred in 3 patients (14%). All patients who lived beyond day+30 successfully engrafted, with a median time to neutrophil recovery of 22 days (range 11-31). The incidence of acute GVHD was 50% in the 16 patients who survived beyond day+30, and chronic GVHD was 50% in the 14 patients who survived beyond day+100. Two patients subsequently developed SGF and both underwent a third allotransplant. Our real-world data confirms that a second allogeneic HSCT for graft failure or poor graft function is associated with high NRM and early mortality. Nonetheless, there are long-term survivors and further studies should focus on reducing NRM in these patients. allogeneic stem cell transplantation graft failure graft rejection poor graft function transplant complications Figures Figure 1 Introduction Graft failure is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT) which is associated with considerable morbidity and mortality. The reported incidence of graft failure in retrospective studies is approximately 5% or less ( 1 – 4 ), but is reported at frequencies of 10–30% in higher risk groups such as patients receiving HSCT from HLA-mismatched donors, with reduced intensity conditioning (RIC), or in umbilical cord transplant (UCB) recipients ( 1 , 2 , 5 , 6 ). The only curative therapy for graft failure is a second allogeneic HSCT (HSCT2). Available data on outcomes after HSCT2 for graft failure is primarily limited to small, heterogeneous retrospective studies with no uniform approach to donor selection, graft source, and conditioning regimen. The outcomes of HSCT2 following graft failure remain poor with reported 5-year (y) overall survival (OS) of 15–30% ( 3 , 7 , 8 ). Similarly, poor graft function following allogeneic HSCT is also associated with worse outcomes. While graft failure is associated with loss of donor chimerism, poor graft function is defined by the presence of full donor chimerism ( 9 ). Although patients with poor graft function are more likely to respond to growth factors or have spontaneous recovery, some may require HSCT2. The outcomes of HSCT2 for poor graft function have not been clearly defined, and these patients were likely included in many studies of HSCT2 for graft failure where chimerism was either not measured or not reported. In this article, we describe the outcomes of patients who underwent HSCT2 for graft failure or poor graft function following an initial HSCT (HSCT1) at our centre in Vancouver, British Columbia over a 20-year time period. Materials and Methods This retrospective study included all adult patients aged ≥ 18 years who underwent HSCT2 for graft failure or poor graft function at our centre between February 2001 and July 2021. Primary graft failure (PGF) was defined as failure to achieve absolute neutrophil count (ANC) ≥ 0.5x10 9 /L by day + 30 post-HSCT (or day + 42 following cord blood transplant) with associated pancytopenia. Secondary graft failure (SGF) was defined as development of significant cytopenias necessitating blood products and/or growth factors, after achieving initial engraftment. We also included patients with poor graft function, defined as multilineage cytopenias requiring transfusion and/or growth factors in the presence of full donor chimerism (> 95%) as well as patients with cytopenias and mixed chimerism( 9 ). Patients with other explanation for pancytopenia such as relapse, infection, or drugs were excluded. For the sake of clarity, all patients in this study will be referred to as having graft failure. Chimerism was assessed using polymerase chain reaction for short tandem repeats or by assessing XX/XY using fluorescence in situ hybridization in sex-mismatched donor–recipient pairs. Neutrophil recovery was defined as the first of 3 consecutive days achieving a neutrophil count of ≥ 0.5 x10 9 /L and platelet recovery as the first of 3 consecutive days achieving a platelet count of ≥ 20 x10 9 /L without transfusion support. Graft-versus-host disease (GVHD) was graded according to the Glucksberg and the National Institutes of Health classification for acute and chronic GVHD respectively ( 10 , 11 ). The analysis was limited to patients living past day + 30 in acute GVHD (aGVHD) and day + 100 in chronic GVHD (cGVHD). Outcomes such as OS, disease free survival (DFS), relapse, and non-relapse mortality (NRM) were defined as time from HSCT2 to event. Early mortality was defined as death prior to day + 30 post-transplant. Survival functions were estimated using the Kaplan-Meier method and compared with the log-rank test. Patients who were alive at last follow-up were censored. All analyses were performed using SPSS version 28 and p-values < 0.05 were considered significant. Results Patient characteristics A total of 21 patients (11 PGF and 10 SGF) were identified. In the 14 of 21 patients in whom chimerism data was available at the time of graft failure, 10 (71%) had loss of donor chimerism, 2 (14%) had mixed chimerism, and 2 (14%) had full donor chimerism. Patients and donor characteristics for HSCT1 and HSCT2 are summarized in Table 1 and Table 2. HSCT1 characteristic s The most common indications for HSCT1 was hematological malignancy, notably acute leukemia in 52% (Table 1). HLA mismatched donors were used in 33% patients. Most patients received peripheral blood stem cells source (PBSC) (81%). One patient received both PBSC and bone marrow stem cells because of insufficient cell dose. Two patients received a stem cell dose lower than CD34+ of 2x10 6 /kg or total nucleated cells (TNC) of 3x10 8 /kg. Among 20 patients with available cryopreservation data, 8 patients received cryopreserved product (38%). A myeloablative conditioning regimen (MAC) was used in 57%. Antithymocyte globuline (ATG) was used in 33%, alemtuzumab in 5%, post-transplant cyclophosphamide (PT-Cy) in 14%; none received ex-vivo T cell depletion. All patients received calcineurin inhibitor (CNI) based GVHD prophylaxis. HSCT2 characteristics The median age at time of HSCT2 was 48 years (range 19-70) (Table 2). Among the 16 patients who had available performance status data at the time of HSCT2, 81% had a KPS ≥80% or ECOG ≥1. The median time between HSCT1 and HSCT2 was 55 days (range 38-168 days) and 278 days (range 75-3074 days) for PGF and SGF, respectively. In those with SGF, the median time from engraftment after HSCT1 to SGF was 97.5 days (range 32-3017) and the median time from diagnosis of SGF to HSCT2 was 52.5 days (range 8-272). Matched unrelated donor (33%) was the most common donor type, followed by haploidentical (29%), matched related (19%), 9/10 mismatched unrelated (14%) and 9/10 mismatched related donor (5%). The same donor as for HSCT1 was used in 24% of transplants. Peripheral blood was the most common stem cell source (81%). The median TNC infused was 13.1 x10 8 /kg (range 0.1-18.5 x10 8 /kg), and median CD34+ cell dose infused was 6.6 x10 6 /kg (range 3.5-20 x10 6 /kg). A cryopreserved product was used in 14%. The most frequently used conditioning regimen for HSCT2 was Cyclophosphamide-ATG+/-low dose total body irradiation (200cGy) (43%); the remainder receiving various RIC regimens. ATG was used in 62% and PT-Cy in 29%. All patients undergoing transplant from a haploidentical donor received PT-Cy. Most patients received CNI-based GVHD prophylaxis with either methotrexate or mofetil mycophenolate. Only 1 patient received methotrexate without CNI. Engraftment Engraftment was achieved in 16/21 patients (76%). All 16 patients who lived beyond day+30 successfully engrafted, with a median time to neutrophil recovery of 22 days (range 11-31 days), and median time to platelet recovery of 28 days (range 13-49 days). GVHD The incidence of aGVHD was 50% in the 16 patients who survived beyond day+30, and cGVHD was 50% in the 14 patients who survived beyond day+100. Grading of GVHD was not possible due to missing data. Infections There were 6 patients (29%) and 1 patient (5%) who developed CMV and EBV viremia requiring treatment, respectively. Survival outcomes The median follow-up for survivors was 120 months (range 7-170 months). Nine patients were alive at time of last follow-up. Median OS was 32 months (95% CI 0-116 months), with 2y OS of 52%, and 5y OS of 46% (Figure 1A). Early mortality before day+30 occurred in 5 patients (24%): the cause of death was sepsis (fungemia in 2, gram negative bacilli in 1 and no microorganism was identified in 1 patient) with multiorgan failure in 4 patient and and hepatic sinusoidal obstruction syndrome in 1 patient. The 5y OS in those surviving past day+100 was 69%. Median DFS was 32 months (95% CI 0-75 months), with 2y DFS of 52% and 5y DFS of 40% (Figure 1B). NRM was the major cause of treatment failure, with a 2y NRM of 48% (Figure 1C). Relapse occurred in 3 patients (14%) (Figure 1D). All the patients who relapsed had a diagnosis of chronic lymphoid leukemia and 2 of them were still alive at the time of last follow-up several years post HSCT2. Of the 12 patients who died, the cause of death was infection in 8 patients (67%), GVHD in 2 (17%), hepatic veno-occlusive disease in 1 (8%), and relapse in 1 (8%). Two patients subsequently developed SGF and both underwent a third allotransplant. Both of these patients had a diagnosis of CLL and both experienced disease relapsed following the third transplant, although one remains alive after over 11 years of follow up. Subgroup analyses There was a trend towards higher NRM and lower OS in patients with PGF compared to those with SGF, but this was not statistically significant. There was also a trend towards better outcomes in patients transplanted between 2011-2021 compared to 2000-2010. The 5y OS was 33% in patients transplanted during the earlier time period compared to 57% in the most recent time period (p=0.130). A total of 6 patients were transplanted during the COVID-19 pandemic (March 2020 onwards). Although the numbers were small, there were no significant differences in DFS, OS, NRM, or relapse among patients transplanted pre- vs during the COVID-19 pandemic. Discussion Patients with graft failure have significant morbidity and mortality post allogeneic HSCT. This single centre retrospective study demonstrates that a second transplant can successfully rescue some patients. Nevertheless, outcomes following HSCT2 remain poor. Prior studies have reported that 1y OS after HSCT2 is approximately 30% ( 8 , 12 – 16 ), but can be as low as 11% ( 17 ). A recent European Society for Blood and Marrow Transplantation (EBMT) registry study of 243 patients undergoing HSCT2 for PGF reported a 5y OS of 30.7% ( 18 ). Similarly, we observed a 5y OS of 46%. Early mortality is frequent and occurred in 24% in our cohort, which is in line with other reports that range from 10–39% ( 15 , 17 , 19 , 23 ). Non-relapse mortality was the major driver of treatment failure across all studies, with many, including our study, reporting 1y NRM around 50% ( 13 , 15 , 18 , 23 ). Infection was the leading cause of death accounting for 67% of fatalities, which is in line with previously published literature ( 8 , 13 , 14 , 16 , 18 – 20 , 23 ). We observed a trend towards better outcomes in the most recent time period (2011–2021 compared to 2000–2011), which is probably multifactorial but improved supportive care and more adapted transplant platform likely playing a role. The optimal transplant platform for HSCT2 remains unknown. The main considerations include promoting engraftment to minimize the duration of cytopenias, reduce the risk of recurrent graft rejection, as well as limiting toxicity. In the current study, neutrophil engraftment was achieved in 76%, and in all 16 patients who lived beyond day + 30, although 2 patients subsequently developed SGF. Previous studies reported highly variable rates of engraftment, ranging from 50–80% ( 13 , 17 , 19 , 23 ). The discrepancy in engraftment rates among different studies is likely influenced by multiple factors such as heterogeneity in stem cell source, stem cell dose, donor type, conditioning regimen, and T-cell depletion. In our report, the most frequently used stem cell source was PBSC in 81% and none received UCB, which may have contributed to the high engraftment rates. Some studies have shown that the use of PBSC is a predictive factor for engraftment after HSCT2 ( 20 , 21 ). Additionally, UCB has been associated with lower neutrophil recovery in many studies, with variable impacts on survival ( 13 , 14 , 20 ). Nevertheless, other reports, such as the recent EBMT registry study by Nagler and al., found no effect of stem cell source or donor type on outcomes of HSCT2 ( 18 ). At our centre, haploidentical donors have been increasingly used for HSCT2 following graft failure because they are widely and rapidly available. Efforts are being made to proceed to transplant as soon as possible to decrease the risk of complications, specifically infections, related to prolonged cytopenias. However, some studies do not show any impact of inter-transplant delay on outcome ( 12 , 15 , 19 ). Ferrà et al. hypothesized that the inter-transplant delays can have paradoxical effects on transplant outcomes by, on one end, increasing the risk of complications associated with prolonged aplasia, but also by selecting for patients who are clinically well and have better prognosis. Interestingly, other studies have found longer inter-transplant time interval of ≥ 60–80 days to be associated with better survival ( 20 – 22 ). There was a trend towards higher NRM in patients with PGF compared to those with SGF, but this was not statistically significant. The underlying explanation behind this observation is likely multifactorial, but longer inter-transplant delay may decrease the compounding toxicity of successive conditioning regimens. Not surprisingly, Nagler et al. observed higher TRM and lower OS in patients who had received MAC during HSCT1 ( 18 ). However, the optimal conditioning regimen for HSCT2 has not been clearly established. The role of conditioning in this context is to decrease the risk of rejection and promote engraftment by suppressing residual host T-cells. To achieve this, full myeloablation may not be necessary as it is also associated with higher toxicity. Several studies have reported patients who achieved successful engraftment after stem cell infusion even without conditioning ( 12 , 14 , 16 , 17 , 19 , 21 ). Moreover, Platzbecker et al. reported data from the German Bone Marrow Center database and found no benefits of using conditioning in 34 patients undergoing HSCT2 for graft failure ( 12 ). Nevertheless, our current practice is to use conditioning to promote engraftment, although we have pivoted to less intensive regimens to reduce toxicity. The limitations of the current study include retrospective study design and small sample size, limited by the rarety of graft failure and single-centre design. Further studies to define the optimal transplant platform for patients undergoing HSCT2 in the context of graft failure, are warranted to further improve outcomes. Conclusion Graft failure is a rare but life-threatening complication post allogeneic transplantation. These data show that a second transplant can successfully rescue around half of the patients with this condition. Similar to prior literature, NRM is the most frequent cause of treatment failure and is primarily due to infection. The optimal transplant platform to maximize engraftment and minimize toxicity has not been dermined. Further studies are needed to improve long term outcomes in patients with graft failure. Abbreviations HSCT: allogeneic hematopoietic stem cell transplantation HSCT1: first allogeneic hematopoietic stem cell transplantation HSCT2: second allogeneic hematopoietic stem cell transplantation GVHD: Graft-versus-host-disease aGVHD: Acute graft-versus-host-disease cGVHD: Chronic graft-versus-host-disease OS: Overall survival NRM: non relapse mortality DFS: disease free survival UBC: umbilical cord transplant PBSC: peripheral blood stem cells source TNC: Total nucleated cells RIC: reduced intensity conditioning MAC: Myeloablative intensity conditioning PGF: Primary graft failure SGF: Secondary graft failure ANC: absolute neutrophil count ATG: Antithymocyte globuline PT-Cy: Post-transplant cyclophosphamide CNI: calcineurin inhibitor EBMT: European Society for Blood and Marrow Transplantation Declarations Ethics approval and consent to participate The project titled “Outcomes following second allogeneic stem cell transplant for graft failure or poor graft function: a single centre experience” was reviewed by the University of British Columbia Research and Ethics Board Chair and the research project was found acceptable on ethical grounds for research involving human subjects and approval was granted (UBC CREB H22-03330). The initial approval date was June 1, 2023. The approval is renewed yearly and the current approval will expire on May 23, 2025. The need for signed consent from individual patient was waived as the risk to confidentiality was deemed minimal. Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: Cherniawsky: Consultancy / Ad board: Astellas, Kite/Gilead, Abbvie. Speakers Honoraria: Astellas, Kite/Gilead. Mourad: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Paladin: Honoraria, Speakers Bureau. Chung: Takeda: Consultancy, Honoraria; Astella Pharma: Honoraria; Novartis: Honoraria; Paladin: Honoraria. Sanford: Astellas: Honoraria; AbbVie: Honoraria. Song: Novartis: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Forus: Honoraria; Gilead: Honoraria. Stubbins: AbbVie: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria. Toze: AbbVie: Honoraria, Research Funding; Beigene: Honoraria; Janssen: Honoraria; Astra-Zeneca: Research Funding. White: Novartis: Honoraria. All other authors have no potential conflicts to disclose. Funding: None Authors' contributions: JLK contributed to data acquisition, analysis, interpretation and drafting of the manuscript. MABJ contributed to data acquisition. SC, HC, DL, DLF, FK, SHN, SN, TJN, JR, DS, KWS, RJS, CLT, JW and YAM participated in data interpretations and revised the manuscript. CR conceptualised the study and contributed to data acquisition, analysis and interprestation as well as revision of the manuscript. All authors read and approved the final manuscript. Acknowledgements: None Artificial intelligence: Artificial intenlligence tools were not used at any stage during the elaboration of this manucript. References Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al. Effect of HLA Compatibility on Engraftment of Bone Marrow Transplants in Patients with Leukemia or Lymphoma. N Engl J Med. 1989 Jan 26;320(4):197–204. Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, et al. Major-Histocompatibility-Complex Class I Alleles and Antigens in Hematopoietic-Cell Transplantation. N Engl J Med. 2001 Dec 20;345(25):1794–800. Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013 Apr;48(4):537–43. 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Tables Table 1. Patient and HSCT1 characteristics (n = 21) Median recipient age (year) 46 (range 18-69) Recipient sex Male Female 13 (61.9%) 8 (38.1%) Performance status ECOG 0-1/KPS 80-100% Unknown Indication for transplant AML ALL MPAL CLL CML MDS Follicular lymphoma Aplastic anemia Krabbe disease 17 (81%) 4 (19%) 9 (42.9%) 1 (4.8%) 1 (4.8%) 4 (19%) 2 (9.5%) 1 (4.8%) 1 (4.8%) 1 (4.8%) 1 (4.8%) Median donor age (years) 38 (range 13-59) Donor sex Male Female Unknown 14 (66.7%) 4 (19.0%) 3 (14.3%) Donor type Matched related (10/10) Matched unrelated (10/10) Mismatched related (9/10) Mismatched unrelated (9/10) Haploidentical 5 (23.8%) 9 (42.8%) 1 (4.8%) 5 (23.8%) 1 (4.8%) ABO compatibility Compatible Minor mismatch Major mismatch Unknown 7 (33.3%) 8 (38.1%) 5 (23.8%) 1 (4.8%) Donor-recipient sex match Male/Male Female/ Female Male/ Female Female/Male 11 (52.4%) 3 (14.3%) 5 (23.8%) 2 (9.5%) Donor-recipient CMV status Neg/Neg Neg/Pos Pos/Neg Pos/Pos 5 (23.8%) 3 (14.3%) 2 (9.5%) 11 (52.4%) Stem cell source Peripheral blood Bone marrow Both peripheral blood and bone marrow Cryopreserved Yes No Unknown 17 (81.0%) 3 (14.3%) 1 (4.8%) 8 (38.1%) 12 (57.1%) 1 (4.8%) Median number of CD34 x 10 6 /kg infused 5.83 (range 1.5-13.1) Median number of TNC x 10 8 /kg infused 8.31 (range 2.4-16.7) Conditioning regimen Cy-TBI+/-ATG Bu-Cy +/- ATG Bu(4)-Flu / ATG Bu(2)-Flu/Alemtuzumab or ATG or PT-Cy TT-Bu-Flu/PT-Cy Flu-TBI Flu-Cy 4 (19%) 6 (28.6%) 1 (4.8%) 6 (28.6%) 1 (4.8%) 1 (4.8%) 2 (9.5%) Conditioning intensity Myeloablative Reduced intensity 12 (57.1%) 9 (42.9%) T cell modulation/ lymphodepletion None ATG PT-Cy Alemtuzumab 10 (47.6%) 7 (33.3%) 3 (14.3%) 1 (4.8%) GVHD prophylaxis CSA-MTX CSA Tac-MMF 18 (85.7%) 2 (9.5%) 1 (4.8%) Table 2. HSCT2 characteristics (n= 21) Median donor age (years) 48 (range 19-70) Donor sex Male Female Performance status ECOG 0-1/KPS 80-100% ECOG 2/KPS 60-70% ECOG 3-4/ KPS <60% Unknown 13 (62.9%) 8 (38.1%) 13 (62.9%) 1 (4.8%) 2 (9.5%) 5 (23.8%) Median time from HSCT1 to HSCT 2 (days) Donor type Matched related (10/10) Matched unrelated (10/10) Mismatched related (9/10) Mismatched unrelated (9/10) Haploidentical 87 (range 38-3074) 4 (19.0%) 7 (33.3%) 1 (4.8%) 3 (14.3%) 6 (28.6%) Same donor as HSCT1 5 (23.8%) ABO compatibility Compatible Minor mismatch Major mismatch Bidirectional Unknown 9 (42.9%) 5 (23.8%) 3 (14.3%) 2 (9.5%) 2 (9.5%) Donor-recipient sex match Male/Male Female/ Female Male/ Female Female/Male 7 (33.3%) 3 (14.3%) 5 (23.8%) 6 (28.6%) Donor-recipient CMV status Neg/Neg Neg/Pos Pos/Neg Pos/Pos 2 (9.5%) 6 (28.6%) 2 (9.5%) 11 (52.4%) Stem cell source Peripheral blood Bone marrow Unknown Cryopreserved Yes No 17 (81%) 2 (9.5%) 2 (9.5%) 3 (14.3%) 18 (85.7%) Median number of CD34 x 10 6 /kg infused 6.56 (range 3.5-20) Median number of TNC x 10 8 /kg infused 13.1 (range 0.1-18.5) Conditioning regimen Cy-ATG +/- TBI(200 cGy) Flu-Treo/ATG Flu-Cy +/- TBI(200 cGy)/PT-Cy Flu-Cy Bu(2)-Flu/PT-Cy Flu-TBI 9 (42.9%) 4 (19%) 4 (19%) 2 (9.5%) 2 (9.5%) 1 (4.8%) Conditioning intensity Myeloablative Reduced intensity 0 (0%) 21 (100%) T cell modulation/ lymphodepletion None ATG PT-Cy 3 (14.3%) 13 (62.0%) 6 (28.6%) GVHD prophylaxis CSA-MTX Tac-MTX Tac-MMF CSA-MMF MTX 11 (52.4%) 1 (4.8%) 6 (28.6%) 2 (9.5%) 1 (4.8%) Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5321463","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":371710472,"identity":"cf8c5f86-440d-4f71-afa2-1291047ab424","order_by":0,"name":"Jowon L. Kim","email":"","orcid":"","institution":"The University of British Columbia","correspondingAuthor":false,"prefix":"","firstName":"Jowon","middleName":"L.","lastName":"Kim","suffix":""},{"id":371710473,"identity":"9f2fa038-1f59-42b7-8dbb-1a1d8c912479","order_by":1,"name":"Moss A. Bruton Joe","email":"","orcid":"","institution":"The University of British Columbia","correspondingAuthor":false,"prefix":"","firstName":"Moss","middleName":"A. Bruton","lastName":"Joe","suffix":""},{"id":371710474,"identity":"e4abf151-b5e6-42f5-a49a-2af6c29b1ff7","order_by":2,"name":"Shanee Chung","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shanee","middleName":"","lastName":"Chung","suffix":""},{"id":371710475,"identity":"05ea9544-1ade-4255-8c06-5aee500dd3d7","order_by":3,"name":"Hannah Cherniawsky","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hannah","middleName":"","lastName":"Cherniawsky","suffix":""},{"id":371710476,"identity":"9d70d9b4-71e0-4198-97b9-60e63354c7f4","order_by":4,"name":"Donna L Forrest","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Donna","middleName":"L","lastName":"Forrest","suffix":""},{"id":371710477,"identity":"e1862025-4e1d-4b9d-8d57-941189c0a4ac","order_by":5,"name":"Florian Kuchenbauer","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Florian","middleName":"","lastName":"Kuchenbauer","suffix":""},{"id":371710478,"identity":"6c1995d1-8103-4e2a-becb-9753fb8a232d","order_by":6,"name":"Deepesh Lad","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Deepesh","middleName":"","lastName":"Lad","suffix":""},{"id":371710479,"identity":"a8a07d83-879e-42e2-92fd-a277b1ac472c","order_by":7,"name":"Stephen H Nantel","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"H","lastName":"Nantel","suffix":""},{"id":371710480,"identity":"c4377267-d456-4111-9f05-8c25bd1dde29","order_by":8,"name":"Sujaatha Narayanan","email":"","orcid":"","institution":"Vancouver General 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Sanford","suffix":""},{"id":371710484,"identity":"0619775f-06cd-49f1-9de9-f7607413f535","order_by":12,"name":"Kevin W Song","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"W","lastName":"Song","suffix":""},{"id":371710485,"identity":"a0fef5cd-1559-45d6-b0c2-c2a026536151","order_by":13,"name":"Ryan J Stubbins","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"J","lastName":"Stubbins","suffix":""},{"id":371710486,"identity":"c91c1987-53bc-41ce-8740-c7752a96ba2a","order_by":14,"name":"Cynthia L Toze","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cynthia","middleName":"L","lastName":"Toze","suffix":""},{"id":371710487,"identity":"79cb236b-8e4d-4c46-9eb4-e93ee393e9b2","order_by":15,"name":"Jennifer White","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"White","suffix":""},{"id":371710488,"identity":"3a149be6-710e-40f5-8ce2-e5574a3543f9","order_by":16,"name":"Yasser Abou Mourad","email":"","orcid":"","institution":"Vancouver General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yasser","middleName":"Abou","lastName":"Mourad","suffix":""},{"id":371710489,"identity":"d8f92aca-c9ba-4e12-b839-720b5ec1c531","order_by":17,"name":"Claudie Roy","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIiWNgGAWjYDACdiDmMQAzGR/DRRkb8GhhRmhhNiZBC4TJJk2UFv5m5mcSbwpsGMzbe8yqC2rs5M3ZDx/7wLjDjoG//QBWLRKH2cwk5xikMcicOWN2e8axZMOdPWnJMxjPJDNInEnAqsWAmcFMmsfgMIOERI7Zbd6GA4wbbvAYMzC2HWAwYMClhf0bUMt/sJZioBb7DTf4P0O08D/AoYUHZMsBsBZmoJZEoC3MEC0S2G2ROMxTbDnHIJlHgudYsTTQL8kbzqQZMySeAYrcwG4Lf3v7xhtv/tjJSbA3b/wMDDHbDccPP2b4uMNOjr8fuy0wAIwaDgMENwEeWXgBO3Z3jIJRMApGwSgAABolUSfQADRpAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9218-5801","institution":"Vancouver General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Claudie","middleName":"","lastName":"Roy","suffix":""}],"badges":[],"createdAt":"2024-10-23 21:29:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5321463/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5321463/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":69437391,"identity":"3d4f740a-4f82-4bfb-82f4-8802d68bb3b3","added_by":"auto","created_at":"2024-11-20 10:47:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":98625,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eOverall survival \u003cstrong\u003e(B) \u003c/strong\u003edisease free survival\u003cstrong\u003e(C) \u003c/strong\u003enon-relapse mortality \u003cstrong\u003e(D) \u003c/strong\u003ecumulative incidence of relapse\u003cstrong\u003e \u003c/strong\u003efollowing second allogeneic stem cell transplantation for graft failure.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5321463/v1/e475dcd4a0adf988344d096c.png"},{"id":75419057,"identity":"04c93349-3a13-4eff-871d-f1b5c87aba4e","added_by":"auto","created_at":"2025-02-04 10:32:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1114549,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5321463/v1/14374efe-ad40-46a2-8332-8d8e80eb3350.pdf"}],"financialInterests":"","formattedTitle":"Outcomes following second allogeneic stem cell transplant for graft failure or poor graft function: a single centre experience","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGraft failure is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT) which is associated with considerable morbidity and mortality. The reported incidence of graft failure in retrospective studies is approximately 5% or less (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), but is reported at frequencies of 10\u0026ndash;30% in higher risk groups such as patients receiving HSCT from HLA-mismatched donors, with reduced intensity conditioning (RIC), or in umbilical cord transplant (UCB) recipients (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The only curative therapy for graft failure is a second allogeneic HSCT (HSCT2). Available data on outcomes after HSCT2 for graft failure is primarily limited to small, heterogeneous retrospective studies with no uniform approach to donor selection, graft source, and conditioning regimen. The outcomes of HSCT2 following graft failure remain poor with reported 5-year (y) overall survival (OS) of 15\u0026ndash;30% (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSimilarly, poor graft function following allogeneic HSCT is also associated with worse outcomes. While graft failure is associated with loss of donor chimerism, poor graft function is defined by the presence of full donor chimerism (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Although patients with poor graft function are more likely to respond to growth factors or have spontaneous recovery, some may require HSCT2. The outcomes of HSCT2 for poor graft function have not been clearly defined, and these patients were likely included in many studies of HSCT2 for graft failure where chimerism was either not measured or not reported.\u003c/p\u003e \u003cp\u003eIn this article, we describe the outcomes of patients who underwent HSCT2 for graft failure or poor graft function following an initial HSCT (HSCT1) at our centre in Vancouver, British Columbia over a 20-year time period.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis retrospective study included all adult patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who underwent HSCT2 for graft failure or poor graft function at our centre between February 2001 and July 2021. Primary graft failure (PGF) was defined as failure to achieve absolute neutrophil count (ANC)\u0026thinsp;\u0026ge;\u0026thinsp;0.5x10\u003csup\u003e9\u003c/sup\u003e/L by day\u0026thinsp;+\u0026thinsp;30 post-HSCT (or day\u0026thinsp;+\u0026thinsp;42 following cord blood transplant) with associated pancytopenia. Secondary graft failure (SGF) was defined as development of significant cytopenias necessitating blood products and/or growth factors, after achieving initial engraftment. We also included patients with poor graft function, defined as multilineage cytopenias requiring transfusion and/or growth factors in the presence of full donor chimerism (\u0026gt;\u0026thinsp;95%) as well as patients with cytopenias and mixed chimerism(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Patients with other explanation for pancytopenia such as relapse, infection, or drugs were excluded. For the sake of clarity, all patients in this study will be referred to as having graft failure.\u003c/p\u003e \u003cp\u003eChimerism was assessed using polymerase chain reaction for short tandem repeats or by assessing XX/XY using fluorescence in situ hybridization in sex-mismatched donor\u0026ndash;recipient pairs. Neutrophil recovery was defined as the first of 3 consecutive days achieving a neutrophil count of \u0026ge;\u0026thinsp;0.5 x10\u003csup\u003e9\u003c/sup\u003e/L and platelet recovery as the first of 3 consecutive days achieving a platelet count of \u0026ge;\u0026thinsp;20 x10\u003csup\u003e9\u003c/sup\u003e/L without transfusion support. Graft-versus-host disease (GVHD) was graded according to the Glucksberg and the National Institutes of Health classification for acute and chronic GVHD respectively (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The analysis was limited to patients living past day\u0026thinsp;+\u0026thinsp;30 in acute GVHD (aGVHD) and day\u0026thinsp;+\u0026thinsp;100 in chronic GVHD (cGVHD).\u003c/p\u003e \u003cp\u003eOutcomes such as OS, disease free survival (DFS), relapse, and non-relapse mortality (NRM) were defined as time from HSCT2 to event. Early mortality was defined as death prior to day\u0026thinsp;+\u0026thinsp;30 post-transplant. Survival functions were estimated using the Kaplan-Meier method and compared with the log-rank test. Patients who were alive at last follow-up were censored. All analyses were performed using SPSS version 28 and p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 21 patients (11 PGF and 10 SGF) were identified. In the 14 of 21 patients in whom chimerism data was available at the time of graft failure, 10 (71%) had loss of donor chimerism, 2 (14%) had mixed chimerism, and 2 (14%) had full donor chimerism. Patients and donor characteristics for HSCT1 and HSCT2 are summarized in Table 1 and Table 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHSCT1 characteristic\u003c/em\u003es\u003c/p\u003e\n\u003cp\u003eThe most common indications for HSCT1 was hematological malignancy, notably acute leukemia in 52% (Table 1). HLA mismatched donors were used in 33% \u0026nbsp;patients. Most patients received peripheral blood stem cells source (PBSC) (81%). One patient received both PBSC and bone marrow stem cells because of insufficient cell dose. Two patients received a stem cell dose lower than CD34+ of 2x10\u003csup\u003e6\u003c/sup\u003e/kg or total nucleated cells (TNC) of 3x10\u003csup\u003e8\u003c/sup\u003e/kg. Among 20 patients with available cryopreservation data, 8 patients received cryopreserved product (38%).\u0026nbsp;A myeloablative conditioning regimen (MAC) was used in 57%. Antithymocyte globuline (ATG) was used in 33%, alemtuzumab in 5%, post-transplant cyclophosphamide (PT-Cy) in 14%; none received ex-vivo T cell depletion. All patients received calcineurin inhibitor (CNI) based GVHD prophylaxis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHSCT2 characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe median age at time of HSCT2 was 48 years (range 19-70) (Table 2). Among the 16 patients who had available performance status data at the time of HSCT2, 81% had a KPS ≥80% or ECOG ≥1. The median time between HSCT1 and HSCT2 was 55 days (range 38-168 days) and 278 days (range 75-3074 days) for PGF and SGF, respectively. In those with SGF, the median time from engraftment after HSCT1 to SGF was 97.5 days (range 32-3017) and the median time from diagnosis of SGF to HSCT2 was 52.5 days (range 8-272).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMatched unrelated donor (33%) was the most common donor type, followed by haploidentical (29%), matched related (19%), 9/10 mismatched unrelated (14%) and 9/10 mismatched related donor (5%). The same donor as for HSCT1 was used in 24% of transplants. Peripheral blood was the most common stem cell source (81%). The median TNC infused was 13.1 x10\u003csup\u003e8\u003c/sup\u003e/kg (range 0.1-18.5 x10\u003csup\u003e8\u003c/sup\u003e/kg), and median CD34+ cell dose infused was 6.6 x10\u003csup\u003e6\u003c/sup\u003e/kg (range 3.5-20 x10\u003csup\u003e6\u003c/sup\u003e/kg). A cryopreserved product was used in 14%.\u003c/p\u003e\n\u003cp\u003eThe most frequently used conditioning regimen for HSCT2 was Cyclophosphamide-ATG+/-low dose total body irradiation (200cGy) (43%); the remainder receiving various RIC regimens. ATG was used in 62% and PT-Cy in 29%. All patients undergoing transplant from a haploidentical donor received PT-Cy. Most patients received CNI-based GVHD prophylaxis with either methotrexate or mofetil mycophenolate. Only 1 patient received methotrexate without CNI.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEngraftment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEngraftment was achieved in 16/21 patients (76%). All 16 patients who lived beyond day+30 successfully engrafted, with a median time to neutrophil recovery of 22 days (range 11-31 days), and median time to platelet recovery of 28 days (range 13-49 days). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGVHD\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence of aGVHD was 50% in the 16 patients who survived beyond day+30, and cGVHD was 50% in the 14 patients who survived beyond day+100. Grading of GVHD was not possible due to missing data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInfections\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere were 6 patients (29%) and 1 patient (5%) who developed CMV and EBV viremia requiring treatment, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSurvival outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up for survivors was 120 months (range 7-170 months). Nine patients were alive at time of last follow-up. Median OS was 32 months (95% CI 0-116 months), with 2y OS of 52%, and 5y OS of 46% (Figure 1A). Early mortality before day+30 occurred in 5 patients (24%): the cause of death was sepsis (fungemia in 2, gram negative bacilli in 1 and no microorganism was identified in 1 patient) with multiorgan failure in 4 patient and and hepatic sinusoidal obstruction syndrome in 1 patient. The 5y OS in those surviving past day+100 was 69%. Median DFS was 32 months (95% CI 0-75 months), with 2y DFS of 52% and 5y DFS of 40% (Figure 1B).\u0026nbsp;NRM was the major cause of treatment failure, with a 2y NRM of 48% (Figure 1C). Relapse occurred in 3 patients (14%) (Figure 1D). All the patients who relapsed had a diagnosis of chronic lymphoid leukemia and 2 of them were still alive at the time of last follow-up several years post HSCT2. Of the 12 patients who died, the cause of death was infection in 8 patients (67%), GVHD in 2 (17%), hepatic veno-occlusive disease in 1 (8%), and relapse in 1 (8%). Two patients subsequently developed SGF and both underwent a third allotransplant. Both of these patients had a diagnosis of CLL and both experienced disease relapsed following the third transplant, although one remains alive after over 11 years of follow up. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSubgroup analyses\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere was a trend towards higher NRM and lower OS in patients with PGF compared to those with SGF, but this was not statistically significant. There was also a trend towards better outcomes in patients transplanted between 2011-2021 compared to 2000-2010. The 5y OS was 33% in patients transplanted during the earlier time period compared to 57% in the most recent time period (p=0.130). A total of 6 patients were transplanted during the COVID-19 pandemic (March 2020 onwards). Although the numbers were small, there were no significant differences in DFS, OS, NRM, or relapse among patients transplanted pre- vs during the COVID-19 pandemic.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with graft failure have significant morbidity and mortality post allogeneic HSCT. This single centre retrospective study demonstrates that a second transplant can successfully rescue some patients. Nevertheless, outcomes following HSCT2 remain poor. Prior studies have reported that 1y OS after HSCT2 is approximately 30% (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), but can be as low as 11% (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). A recent European Society for Blood and Marrow Transplantation (EBMT) registry study of 243 patients undergoing HSCT2 for PGF reported a 5y OS of 30.7% (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Similarly, we observed a 5y OS of 46%. Early mortality is frequent and occurred in 24% in our cohort, which is in line with other reports that range from 10\u0026ndash;39% (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Non-relapse mortality was the major driver of treatment failure across all studies, with many, including our study, reporting 1y NRM around 50% (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Infection was the leading cause of death accounting for 67% of fatalities, which is in line with previously published literature (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). We observed a trend towards better outcomes in the most recent time period (2011\u0026ndash;2021 compared to 2000\u0026ndash;2011), which is probably multifactorial but improved supportive care and more adapted transplant platform likely playing a role.\u003c/p\u003e \u003cp\u003eThe optimal transplant platform for HSCT2 remains unknown. The main considerations include promoting engraftment to minimize the duration of cytopenias, reduce the risk of recurrent graft rejection, as well as limiting toxicity. In the current study, neutrophil engraftment was achieved in 76%, and in all 16 patients who lived beyond day\u0026thinsp;+\u0026thinsp;30, although 2 patients subsequently developed SGF. Previous studies reported highly variable rates of engraftment, ranging from 50\u0026ndash;80% (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The discrepancy in engraftment rates among different studies is likely influenced by multiple factors such as heterogeneity in stem cell source, stem cell dose, donor type, conditioning regimen, and T-cell depletion. In our report, the most frequently used stem cell source was PBSC in 81% and none received UCB, which may have contributed to the high engraftment rates. Some studies have shown that the use of PBSC is a predictive factor for engraftment after HSCT2 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Additionally, UCB has been associated with lower neutrophil recovery in many studies, with variable impacts on survival (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Nevertheless, other reports, such as the recent EBMT registry study by Nagler and al., found no effect of stem cell source or donor type on outcomes of HSCT2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAt our centre, haploidentical donors have been increasingly used for HSCT2 following graft failure because they are widely and rapidly available. Efforts are being made to proceed to transplant as soon as possible to decrease the risk of complications, specifically infections, related to prolonged cytopenias. However, some studies do not show any impact of inter-transplant delay on outcome (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Ferr\u0026agrave; et al. hypothesized that the inter-transplant delays can have paradoxical effects on transplant outcomes by, on one end, increasing the risk of complications associated with prolonged aplasia, but also by selecting for patients who are clinically well and have better prognosis. Interestingly, other studies have found longer inter-transplant time interval of \u0026ge;\u0026thinsp;60\u0026ndash;80 days to be associated with better survival (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere was a trend towards higher NRM in patients with PGF compared to those with SGF, but this was not statistically significant. The underlying explanation behind this observation is likely multifactorial, but longer inter-transplant delay may decrease the compounding toxicity of successive conditioning regimens. Not surprisingly, Nagler et al. observed higher TRM and lower OS in patients who had received MAC during HSCT1 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). However, the optimal conditioning regimen for HSCT2 has not been clearly established. The role of conditioning in this context is to decrease the risk of rejection and promote engraftment by suppressing residual host T-cells. To achieve this, full myeloablation may not be necessary as it is also associated with higher toxicity. Several studies have reported patients who achieved successful engraftment after stem cell infusion even without conditioning (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Moreover, Platzbecker et al. reported data from the German Bone Marrow Center database and found no benefits of using conditioning in 34 patients undergoing HSCT2 for graft failure (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Nevertheless, our current practice is to use conditioning to promote engraftment, although we have pivoted to less intensive regimens to reduce toxicity.\u003c/p\u003e \u003cp\u003eThe limitations of the current study include retrospective study design and small sample size, limited by the rarety of graft failure and single-centre design. Further studies to define the optimal transplant platform for patients undergoing HSCT2 in the context of graft failure, are warranted to further improve outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eGraft failure is a rare but life-threatening complication post allogeneic transplantation. These data show that a second transplant can successfully rescue around half of the patients with this condition. Similar to prior literature, NRM is the most frequent cause of treatment failure and is primarily due to infection. The optimal transplant platform to maximize engraftment and minimize toxicity has not been dermined. Further studies are needed to improve long term outcomes in patients with graft failure.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHSCT: allogeneic hematopoietic stem cell transplantation\u003c/p\u003e\n\u003cp\u003eHSCT1: first allogeneic hematopoietic stem cell transplantation\u003c/p\u003e\n\u003cp\u003eHSCT2: second allogeneic hematopoietic stem cell transplantation\u003c/p\u003e\n\u003cp\u003eGVHD: Graft-versus-host-disease\u003c/p\u003e\n\u003cp\u003eaGVHD: Acute graft-versus-host-disease\u003c/p\u003e\n\u003cp\u003ecGVHD: Chronic graft-versus-host-disease\u003c/p\u003e\n\u003cp\u003eOS: Overall survival\u003c/p\u003e\n\u003cp\u003eNRM: non relapse mortality\u003c/p\u003e\n\u003cp\u003eDFS: disease free survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUBC: umbilical cord transplant\u003c/p\u003e\n\u003cp\u003ePBSC: peripheral blood stem cells source\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTNC: Total nucleated cells\u003c/p\u003e\n\u003cp\u003eRIC: reduced intensity conditioning\u003c/p\u003e\n\u003cp\u003eMAC: Myeloablative intensity conditioning\u003c/p\u003e\n\u003cp\u003ePGF: Primary graft failure\u003c/p\u003e\n\u003cp\u003eSGF: Secondary graft failure\u003c/p\u003e\n\u003cp\u003eANC: absolute neutrophil count\u003c/p\u003e\n\u003cp\u003eATG: Antithymocyte globuline\u003c/p\u003e\n\u003cp\u003ePT-Cy: Post-transplant cyclophosphamide\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCNI: calcineurin inhibitor\u003c/p\u003e\n\u003cp\u003eEBMT: European Society for Blood and Marrow Transplantation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe project titled “Outcomes following second allogeneic stem cell transplant for graft failure or poor graft function: a single centre experience”\u0026nbsp;was reviewed by the University of British Columbia Research and Ethics Board Chair\u0026nbsp;and the research project was found acceptable on ethical grounds for research involving human subjects and approval was granted (UBC CREB H22-03330). The initial approval date was June 1, 2023. The approval is renewed yearly and the current approval will expire on May 23, 2025. The need for signed consent from individual patient was waived as the risk to confidentiality was deemed minimal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCherniawsky: Consultancy / Ad board: Astellas, Kite/Gilead, Abbvie. Speakers Honoraria: Astellas, Kite/Gilead.\u003c/p\u003e\n\u003cp\u003eMourad: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Paladin: Honoraria, Speakers Bureau.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChung: Takeda: Consultancy, Honoraria; Astella Pharma: Honoraria; Novartis: Honoraria; Paladin: Honoraria. Sanford: Astellas: Honoraria; AbbVie: Honoraria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSong: Novartis: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Forus: Honoraria; Gilead: Honoraria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStubbins: AbbVie: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eToze: AbbVie: Honoraria, Research Funding; Beigene: Honoraria; Janssen: Honoraria; Astra-Zeneca: Research Funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhite: Novartis: Honoraria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll other authors have no potential conflicts to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJLK contributed to data acquisition, analysis, interpretation and drafting of the manuscript. MABJ contributed to data acquisition. SC, HC, DL, DLF, FK, SHN, SN, TJN, JR, DS, KWS, RJS, CLT, JW and YAM participated in data interpretations and revised the manuscript. CR conceptualised the study and contributed to data acquisition, analysis and interprestation as well as revision of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eArtificial intelligence:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eArtificial intenlligence tools were not used at any stage during the elaboration of this manucript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAnasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al. Effect of HLA Compatibility on Engraftment of Bone Marrow Transplants in Patients with Leukemia or Lymphoma. N Engl J Med. 1989 Jan 26;320(4):197\u0026ndash;204. \u003c/li\u003e\n\u003cli\u003ePetersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, et al. Major-Histocompatibility-Complex Class I Alleles and Antigens in Hematopoietic-Cell Transplantation. N Engl J Med. 2001 Dec 20;345(25):1794\u0026ndash;800. \u003c/li\u003e\n\u003cli\u003eOlsson R, Remberger M, Schaffer M, Berggren DM, Svahn BM, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013 Apr;48(4):537\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003ePark JH, Lee JH, Lee JH, Park HS, Choi EJ, Kang YA, et al. Incidence, Management, and Prognosis of Graft Failure and Autologous Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. J Korean Med Sci. 2021 May 11;36(23):e151. \u003c/li\u003e\n\u003cli\u003eLee KH, Lee JH, Choi SJ, Lee JH, Kim S, Seol M, et al. Failure of trilineage blood cell reconstitution after initial neutrophil engraftment in patients undergoing allogeneic hematopoietic cell transplantation \u0026ndash; frequency and outcomes. Bone Marrow Transplant. 2004 Apr;33(7):729\u0026ndash;34. \u003c/li\u003e\n\u003cli\u003eSatwani P, Jin Z, Duffy D, Morris E, Bhatia M, Garvin JH, et al. Transplantation-Related Mortality, Graft Failure, and Survival after Reduced-Toxicity Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation in 100 Consecutive Pediatric Recipients. Biol Blood Marrow Transplant. 2013 Apr 1;19(4):552\u0026ndash;61. \u003c/li\u003e\n\u003cli\u003eOlsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ, et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015 Aug;29(8):1754\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eRond\u0026oacute;n G, Saliba RM, Khouri I, Giralt S, Chan K, Jabbour E, et al. Long-term follow-up of patients who experienced graft failure postallogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2008 Aug;14(8):859\u0026ndash;66. \u003c/li\u003e\n\u003cli\u003eKharfan-Dabaja MA, Kumar A, Ayala E, Aljurf M, Nishihori T, Marsh R, et al. Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy. Transplant Cell Ther. 2021 Aug;27(8):642\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eGlucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974 Oct;18(4):295\u0026ndash;304. \u003c/li\u003e\n\u003cli\u003eFilipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2005 Dec;11(12):945\u0026ndash;56. \u003c/li\u003e\n\u003cli\u003ePlatzbecker U, Binder M, Schmid C, Rutt C, Ehninger G, Bornh\u0026auml;user M. Second donation of hematopoietic stem cells from unrelated donors for patients with relapse or graft failure after allogeneic transplantation. Haematologica. 2008 Aug 1;93(8):1276\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eHarada K, Fuji S, Seo S, Kanda J, Ueki T, Kimura F, et al. Comparison of the outcomes after haploidentical and cord blood salvage transplantations for graft failure following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2020 Sep;55(9):1784\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eFuji S, Nakamura F, Hatanaka K, Taniguchi S, Sato M, Mori SI, et al. Peripheral blood as a preferable source of stem cells for salvage transplantation in patients with graft failure after cord blood transplantation: a retrospective analysis of the registry data of the Japanese Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2012 Sep;18(9):1407\u0026ndash;14. \u003c/li\u003e\n\u003cli\u003eWaki F, Masuoka K, Fukuda T, Kanda Y, Nakamae M, Yakushijin K, et al. Feasibility of Reduced-Intensity Cord Blood Transplantation as Salvage Therapy for Graft Failure: Results of a Nationwide Survey of Adult Patients. Biol Blood Marrow Transplant. 2011 Jun 1;17(6):841\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eLund TC, Liegel J, Bejanyan N, Orchard PJ, Cao Q, Tolar J, et al. Second Allogeneic Hematopoietic Cell Transplantation For Graft Failure: Poor Outcomes for Neutropenic Graft Failure. Am J Hematol. 2015 Oct;90(10):892\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eSchriber J, Agovi MA, Ho V, Ballen KK, Bacigalupo A, Lazarus HM, et al. Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure. Biol Blood Marrow Transplant. 2010 Aug 1;16(8):1099\u0026ndash;106. \u003c/li\u003e\n\u003cli\u003eNagler A, Labopin M, Swoboda R, Kulagin A, Velardi A, Sanz J, et al. Long-term outcome of second allogeneic hematopoietic stem cell transplantation (HSCT2) for primary graft failure in patients with acute leukemia in remission: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2023 Sep;58(9):1008\u0026ndash;16. \u003c/li\u003e\n\u003cli\u003eFerr\u0026agrave; C, Sanz J, D\u0026iacute;az-P\u0026eacute;rez MA, Morgades M, Gayoso J, Cabrera JR, et al. Outcome of graft failure after allogeneic stem cell transplant: study of 89 patients. Leuk Lymphoma. 2015 Mar 4;56(3):656\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eGuardiola P, Kuentz M, Garban F, Blaise D, Reiffers J, Attal M, et al. Second early allogeneic stem cell transplantations for graft failure in acute leukaemia, chronic myeloid leukaemia and aplastic anaemia. French Society of Bone Marrow Transplantation. Br J Haematol. 2000 Oct;111(1):292\u0026ndash;302. \u003c/li\u003e\n\u003cli\u003eHoran JT, Carreras J, Tarima S, Camitta BM, Gale RP, Hale GA, et al. Risk Factors Affecting Outcome of Second HLA-Matched Sibling Donor Transplantations for Graft Failure in Severe Acquired Aplastic Anemia. Biol Blood Marrow Transplant. 2009 May 1;15(5):626\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eMcCann SR, Bacigalupo A, Gluckman E, Hinterberger W, Hows J, Ljungman P, et al. Graft rejection and second bone marrow transplants for acquired aplastic anaemia: a report from the Aplastic Anaemia Working Party of the European Bone Marrow Transplant Group. Bone Marrow Transplant. 1994 Mar;13(3):233\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eKongtim P, Bittencourt M, Srour SA, Ramdial J, Rondon G, Chen J, et al. Haploidentical transplants for patients with graft failure after the first allograft. Am J Hematol. 2020 Oct;95(10):E267-E269.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Patient and HSCT1 characteristics (n = 21)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian recipient age (year)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e46 (range 18-69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRecipient sex\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (61.9%)\u003c/p\u003e\n \u003cp\u003e8 (38.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePerformance status\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;ECOG 0-1/KPS 80-100%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Unknown\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eIndication for transplant\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAML\u003c/p\u003e\n \u003cp\u003eALL\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMPAL\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCLL\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCML\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMDS\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFollicular lymphoma\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAplastic anemia\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eKrabbe disease \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (81%)\u003c/p\u003e\n \u003cp\u003e4 (19%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (42.9%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e4 (19%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian donor age (years)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e38 (range 13-59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDonor sex\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eMale\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;\u003c/strong\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (66.7%)\u003c/p\u003e\n \u003cp\u003e4 (19.0%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDonor type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMatched related (10/10)\u003c/p\u003e\n \u003cp\u003eMatched unrelated (10/10)\u003c/p\u003e\n \u003cp\u003eMismatched related (9/10)\u003c/p\u003e\n \u003cp\u003eMismatched unrelated (9/10)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Haploidentical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003cp\u003e9 (42.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eABO compatibility\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCompatible\u003c/p\u003e\n \u003cp\u003eMinor mismatch\u003c/p\u003e\n \u003cp\u003eMajor mismatch\u003c/p\u003e\n \u003cp\u003eUnknown\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (33.3%)\u003c/p\u003e\n \u003cp\u003e8 (38.1%)\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDonor-recipient sex match\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale/Male\u003c/p\u003e\n \u003cp\u003eFemale/ Female\u003c/p\u003e\n \u003cp\u003eMale/ Female\u003c/p\u003e\n \u003cp\u003eFemale/Male\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDonor-recipient CMV status\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNeg/Neg\u003c/p\u003e\n \u003cp\u003eNeg/Pos\u003c/p\u003e\n \u003cp\u003ePos/Neg\u003c/p\u003e\n \u003cp\u003ePos/Pos\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStem cell source\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePeripheral blood\u003c/p\u003e\n \u003cp\u003eBone marrow\u003c/p\u003e\n \u003cp\u003eBoth peripheral blood and bone marrow\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCryopreserved\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (81.0%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (38.1%)\u003c/p\u003e\n \u003cp\u003e12 (57.1%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian number of CD34 x 10\u003csup\u003e6\u003c/sup\u003e/kg infused\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e5.83 (range 1.5-13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian number of TNC x 10\u003csup\u003e8\u003c/sup\u003e/kg infused\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e8.31 (range 2.4-16.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConditioning regimen\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCy-TBI+/-ATG\u003c/p\u003e\n \u003cp\u003eBu-Cy +/- ATG\u003c/p\u003e\n \u003cp\u003eBu(4)-Flu / ATG\u003c/p\u003e\n \u003cp\u003eBu(2)-Flu/Alemtuzumab or ATG or PT-Cy\u003c/p\u003e\n \u003cp\u003eTT-Bu-Flu/PT-Cy\u003c/p\u003e\n \u003cp\u003eFlu-TBI\u003c/p\u003e\n \u003cp\u003eFlu-Cy\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (19%)\u003c/p\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConditioning intensity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMyeloablative\u003c/p\u003e\n \u003cp\u003eReduced intensity\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (57.1%)\u003c/p\u003e\n \u003cp\u003e9 (42.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT cell modulation/ lymphodepletion\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003cp\u003eATG\u003c/p\u003e\n \u003cp\u003ePT-Cy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Alemtuzumab\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (47.6%)\u003c/p\u003e\n \u003cp\u003e7 (33.3%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65.5109%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGVHD prophylaxis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCSA-MTX\u003c/p\u003e\n \u003cp\u003eCSA\u003c/p\u003e\n \u003cp\u003eTac-MMF\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.4891%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (85.7%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. HSCT2 characteristics (n= 21)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian donor age (years)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e48 (range 19-70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDonor sex\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eMale\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePerformance status\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;ECOG 0-1/KPS 80-100%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;ECOG 2/KPS 60-70%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;ECOG 3-4/ KPS \u0026lt;60%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (62.9%)\u003c/p\u003e\n \u003cp\u003e8 (38.1%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (62.9%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian time from HSCT1 to HSCT 2 (days)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDonor type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMatched related (10/10)\u003c/p\u003e\n \u003cp\u003eMatched unrelated (10/10)\u003c/p\u003e\n \u003cp\u003eMismatched related (9/10)\u003c/p\u003e\n \u003cp\u003eMismatched unrelated (9/10)\u003c/p\u003e\n \u003cp\u003eHaploidentical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e87 (range 38-3074)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (19.0%)\u003c/p\u003e\n \u003cp\u003e7 (33.3%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSame donor as HSCT1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eABO compatibility\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCompatible\u003c/p\u003e\n \u003cp\u003eMinor mismatch\u003c/p\u003e\n \u003cp\u003eMajor mismatch\u003c/p\u003e\n \u003cp\u003eBidirectional\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (42.9%)\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDonor-recipient sex match\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMale/Male\u003c/p\u003e\n \u003cp\u003eFemale/ Female\u003c/p\u003e\n \u003cp\u003eMale/ Female\u003c/p\u003e\n \u003cp\u003eFemale/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (33.3%)\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e5 (23.8%)\u003c/p\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDonor-recipient CMV status\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNeg/Neg\u003c/p\u003e\n \u003cp\u003eNeg/Pos\u003c/p\u003e\n \u003cp\u003ePos/Neg\u003c/p\u003e\n \u003cp\u003ePos/Pos\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStem cell source\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePeripheral blood\u003c/p\u003e\n \u003cp\u003eBone marrow\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCryopreserved\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (81%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e18 (85.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian number of CD34 x 10\u003csup\u003e6\u003c/sup\u003e/kg infused\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e6.56 (range 3.5-20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian number of TNC x 10\u003csup\u003e8\u003c/sup\u003e/kg infused\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e13.1 (range 0.1-18.5)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConditioning regimen\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCy-ATG +/- TBI(200 cGy)\u003c/p\u003e\n \u003cp\u003eFlu-Treo/ATG\u003c/p\u003e\n \u003cp\u003eFlu-Cy +/- TBI(200 cGy)/PT-Cy\u003c/p\u003e\n \u003cp\u003eFlu-Cy\u003c/p\u003e\n \u003cp\u003eBu(2)-Flu/PT-Cy\u003c/p\u003e\n \u003cp\u003eFlu-TBI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (42.9%)\u003c/p\u003e\n \u003cp\u003e4 (19%)\u003c/p\u003e\n \u003cp\u003e4 (19%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eConditioning intensity\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMyeloablative\u003c/p\u003e\n \u003cp\u003eReduced intensity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e21 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eT cell modulation/ lymphodepletion\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003cp\u003eATG\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; PT-Cy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003cp\u003e13 (62.0%)\u003c/p\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 69.0385%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGVHD prophylaxis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCSA-MTX\u003c/p\u003e\n \u003cp\u003eTac-MTX\u003c/p\u003e\n \u003cp\u003eTac-MMF\u003c/p\u003e\n \u003cp\u003eCSA-MMF\u003c/p\u003e\n \u003cp\u003eMTX\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30.9615%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"allogeneic stem cell transplantation, graft failure, graft rejection, poor graft function, transplant complications","lastPublishedDoi":"10.21203/rs.3.rs-5321463/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5321463/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGraft failure is a rare but life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). We aim to review the outcomes of patients who underwent a second allogeneic HSCT (HSCT2) for graft failure or poor graft function following a previous allogeneic HSCT (HSCT1) at our centre. This restrospectve study included adult patients receiving HSCT2 for graft failure or poor graft function between February 2001 and July 2021. Survival functions were estimated using the Kaplan-Meier method.\u003c/p\u003e\n\u003cp\u003eTwenty-one patients were identified, 11 with primary and 10 with secondary graft failure. In the 14 patients for whom chimerism data was available, 10 had loss of donor chimerism, 2 had mixed chimerism, and 2 had full donor chimerism. The median time between HSCT1 and HSCT2 was 55 days (range 38-168 days) and 278 days (range 75-3074 days) for PGF and SGF, respectively. \u0026nbsp;For HSCT2, matched unrelated donor was the most common donor type (33%) and the same donor as HSCT1 was used in 24%. Most patient received peripheral blood stem cell source (81%) and reduced intensity conditioning (100%) for HSCT2. Graft-versus-host-disease (GVHD) prophylaxis was calcineurin inhibitor-based with either methotrexate or mucophenolate mofetil.\u003c/p\u003e\n\u003cp\u003eThe median follow-up for survivors was 120 months (range 7-170). Overall survival was 52% at 2 years, and 46% at 5 years. Death before day+30 occurred in 5 patients (24%). Non-relapse mortality (NRM) was the major cause of treatment failure, with 2-year NRM of 48%. Infectious complications was the most common cause of death. Relapse occurred in 3 patients (14%). All patients who lived beyond day+30 successfully engrafted, with a median time to neutrophil recovery of 22 days (range 11-31). The incidence of acute GVHD was 50% in the 16 patients who survived beyond day+30, and chronic GVHD was 50% in the 14 patients who survived beyond day+100. Two patients subsequently developed SGF and both underwent a third allotransplant.\u003c/p\u003e\n\u003cp\u003eOur real-world data confirms that a second allogeneic HSCT for graft failure or poor graft function is associated with high NRM and early mortality. Nonetheless, there are long-term survivors and further studies should focus on reducing NRM in these patients.\u003c/p\u003e","manuscriptTitle":"Outcomes following second allogeneic stem cell transplant for graft failure or poor graft function: a single centre experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 10:39:30","doi":"10.21203/rs.3.rs-5321463/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d60c0d9f-6aea-4bf7-90f9-f4f70b3293cf","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-04T10:24:23+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-20 10:39:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5321463","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5321463","identity":"rs-5321463","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}