Reduced-intensity Conditioning Hematopoietic Stem Cell Transplantation Research Articles

Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I-BFM Study Group.

This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival.

Role of abatacept in the prevention of graft-versus-host disease: current perspectives.

Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus-host-disease (GvHD) in mouse models associated with allogeneic hematopoietic stem cell transplant (HSCT). This strategy has recently been adopted in clinical practice for GvHD prevention in human allogeneic HSCT and offers a unique approach to optimizing GvHD prophylaxis following alternative donor HSCTs. When combined with calcineurin inhibitors and methotrexate, abatacept had shown to be safe and effective in preventing moderate to severe acute GvHD in myeloablative HSCT using human leukocyte antigen (HLA) unrelated donors. Equivalent results are being reported in recent studies using alternative donors, in reduced-intensity conditioning HSCT and nonmalignant disorders. These observations have led to hypothesizing that even in the setting of increasing donor HLA disparity, abatacept when given with traditional GvHD prophylaxis does not worsen general outcomes. In addition, in limited studies, abatacept have being protective against the development of chronic GvHD through extended dosing and in the treatment of steroid-refractory chronic GvHD. This review summarized all the limited reports of this novels approach in the HSCT setting.

Intensity of Induction Regimen and Outcomes Among Adults with Ph+ ALL Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Tyrosine kinase inhibitors (TKIs) have facilitated the development of low intensity induction regimens for Philadelphia-chromosome positive (Ph+) ALL. Whether the use of a low intensity induction regimen prior to allogeneic hematopoietic stem cell transplant (HSCT) impacts post-HSCT outcomes is not known. We studied patients with Ph+ ALL receiving HSCT in CR1 at our center to assess the impact of induction treatment intensity on post-HSCT outcomes. Methods We identified consecutive adult patients with Ph+ ALL who underwent HSCT in CR1 between January 1, 2010 and April 31, 2021. Induction therapy was classified as low intensity (TKI, corticosteroid, with or without vincristine) or high intensity (all others). Pre-HSCT measurable residual disease negative (MRDneg) status was determined by BCR::ABL1 RT-PCR and/or via multi-parameter flow cytometry with sensitivity of at least 4.7 and 4 logs respectively. Comparisons between variables were assessed using the Fisher exact (categorical) or Wilcoxon rank-sum (continuous) tests. Overall survival (OS) was defined as time from HSCT to death. Disease-free survival (DFS) was defined as time from HSCT to hematologic relapse or death. The OS and DFS analyses were performed using Cox proportional hazards regression, and differences were assessed using the log rank test. The cumulative incidence of relapse (CIR) was compared between the high versus low intensity induction therapy groups from the time of transplant, with non-relapse mortality (NRM) a competing event. Results A total of 87 patients with Ph+ ALL transplanted in CR1 were identified. Patients in the low intensity induction cohort (n=44, 51%) were older (median 60 vs 47 yrs, p<0.01) and more frequently diagnosed after 2015 (73% vs 33%, p<0.01) compared to patients in the high intensity cohort (n=43, 49%). Clinical and pathologic characteristics including initial white blood cell count, presence of central nervous system disease, BCR::ABL1 transcript type (p190 vs. p210), and presence of additional cytogenetic abnormalities did not differ between groups. There was no difference between the low and high induction intensity cohorts in the proportion of patients requiring a salvage regimen to achieve CR1 (14% vs. 16%, p=0.77). Following induction, molecular MRDneg status was similar in the low and high intensity cohorts (54% and 52% respectively, p=0.99). Most patients proceeded directly to alloHSCT after their initial treatment regimen with similar time to alloHSCT from Ph+ ALL diagnosis in both low and high intensity groups (4 vs. 5 months, p=0.93). Patients receiving low intensity induction were numerically more likely to receive a reduced intensity conditioning (RIC) HSCT (39% vs. 19%, p=0.06). At a median follow-up of 21 months from HSCT, there was no difference between low and high intensity induction with respect to 2-yr DFS (58% vs. 56%, p=0.58), 2-yr OS (62% vs. 63%, p=0.46), 2-yr CIR (9% vs. 17%, p=0.78), and 2yr NRM (33% vs. 29%, p=0.54). A comparison among the low intensity subgroup receiving myeloablative conditioning (MAC) vs. RIC showed no statistically significant difference in OS (HR, 1.02; 95% CI, 0.41-2.54; p=0.97). We segmented patients by pre-HSCT induction intensity and transplant conditioning intensity in the following categories: high intensity induction with MAC HSCT, high intensity induction with RIC HSCT, low intensity induction with MAC HSCT, and low intensity induction with RIC HSCT. Log-rank tests across the four groups showed no significant difference in 2-year DFS (p=0.40), 2-year OS (p=0.19), 2-year CIR (p=0.21), and 2-year NRM (p=0.76). Conclusion Among adult Ph+ ALL patients transplanted in CR1, the intensity of initial induction regimen does not appear to impact post-HSCT outcomes supporting the use of low intensity induction regimens prior to curative HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Acute kidney injury after allogeneic hematopoietic stem cell transplantation – Predictors and survival impact: A single center retrospective study

Introduction and objectivesAcute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. Patients and methodsWe performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. ResultsAKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. ConclusionPatients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.

P1381: EARLY FULL DONOR CHIMERISM AFTER FLAMSA RIC BASED ALLOGENEIC HSCT BUT NOT PRESENCE OF MORPHOLOGICAL REMISSION ASSOCIATES WITH OUTCOMES IN R/R AML PATIENTS

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is still the only potentially curative treatment for patients (pts) with high-risk acute myeloid leukemia (AML). Despite recent advances, a significant number of pts are primary refractory or have early relapse (r/r) with <6 months (m) remission duration. One strategy to improve the outcomes of r/r AML is to perform HSCT after aplasia-inducing chemotherapy. Here, we report on a series of pts receiving a sequential chemotherapy regimen (fludarabine 30 mg/m2, amsacrine 100 mg/m2, cytarabine 2 g/m2 (FLAMSA)) and reduced-intensity conditioning (RIC) followed by HSCT as well as prophylactic donor lymphocyte infusions (DLI) as described by Schmid et al (JCO 2005). Aims: We aimed to retrospectively analyze the outcome of 82 consecutive pts with r/r AML who underwent FLAMSA RIC based HSCT between 2006 and 2020 at our center. Methods: Median age of the 82 pts was 55 years (y) and 38 pts (46%) were male. ELN risk and revised MRC prognostic classification at diagnosis were favorable in 8% and 4%, intermediate in 28% and 56%, and adverse in 64% and 40% of the pts, respectively. Median time from diagnosis to HSCT was 5 months. At the time of HSCT, only 3 pts (3%) were in complete remission (CR). RIC following the FLAMSA chemotherapy was 4Gy TBI and cyclophosphamide (73%), busulfan and cyclophosphamide (11%), melphalan (13%) or 2Gy TBI only (2%). 95% of pts received peripheral blood stem cells and 5% bone marrow (BM) from a matched unrelated donor (MUD, 63%), matched sibling donor (MSD, 10%), mismatch unrelated donor (MMUD, 23%) or a haploidentical donor (4%). Immunosuppression (IS) consisted of cyclosporine A, mycophenolate mofetil and antithymocyte globuline (MUD and MMUD only) or post transplantation cyclophosphamide, tacrolimus and MMF (haplo-donors only). 12 pts (15%) received ≥ 1 DLI preemptively past d+120 as planned. Results: Median overall survival (OS) and event-free survival (EFS) were 276 and 135 days (d). 33 pts (39%) had an OS >1y, and 22 (27%) an event free survival (EFS) >1y. 49 pts (59%) relapsed within the 1st y. Age at HSCT, type of AML (de novo vs secondary), remission status at time of HSCT, ratio of blasts in blood to bone marrow, donor type, type of RIC, mismatch and MRC risk classification had no significant impact on OS and EFS, whereas the number of treatment lines before HSCT significantly influenced OS (p=.05). Pts with ELN favorable/intermediate risk had longer EFS (p=.04, Figure 1A), but not OS (p=.12). On d+28 after HSCT, 43 pts (52%) had reached morphologic leukemia free state (MLFS), CR with incomplete count recovery (CRi) or CR, which was not associated with better OS or EFS (Figure 1B). In contrast, pts (n=49, 60%) with a donor chimerism (DC) ≥98% in BM had a significantly longer EFS (p<.01, Figure 1C) and OS (p<.01) than those with <98%. At d+100 32 pts (39%) were in MLFS, CRi or CR, and had a significant better for EFS (p<.01, Figure 1D) and OS (p<.05). Pts with a d+100 DC ≥98% in BM also had improved EFS (p=.02, Figure 1E) but not OS (p=.16). Acute Graft-versus-Host-Disease (GvHD) °II-IV occurred in 21 pts (26%). 13 pts (16%) developed any grade of chronic GvHD. Incidence of GvHD did not increase after DLI. Image:Summary/Conclusion: Despite the poor prognosis of r/r AML, a significant number of pts after FLAMSA RIC HSCT survived >1 y. Except ELN risk classification, there was no strong outcome predictor prior to HSCT. D+28 DC but not morphological remission in BM identifies pts at high risk for relapse after HSCT, allowing for additional post-HSCT strategies.

Acute kidney injury after allogeneic hematopoietic stem cell transplantation – Predictors and survival impact: A single center retrospective study

Introduction and objectivesAcute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. Patients and methodsWe performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. ResultsAKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. ConclusionPatients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.

Assessment Of The Hematopoietic Cell Transplantation Comorbidity Index In Older Patients Receiving Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for malignant and nonmalignant hematologic disorders. Reduced-intensity conditioning (RIC) regimens have expanded the use of HSCT to elderly and higher risk patients. However, HSCT still remains associated with a significant mortality and morbidity and the careful assessment of risks and benefits before transplantation is essential. Major factors which influence non-relapse mortality (NRM) and overall survival (OS) after HSCT are diagnosis, type of transplant, remission status and the patient's risk profile, which includes age and presence of comorbidities. The use of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been proposed to predict the probability of NRM and OS following HSCT. However, the HCT-CI usefulness for older patients receiving a reduced intensity allogeneic HSCT remains unclear. MethodsA retrospective medical record review was performed to collect data from patients who underwent an allogeneic HSCT at a large, urban, NCI Comprehensive Cancer Center during a five year period (January 2005 to December 2010). Patients 55 years and older who were transplanted using RIC for a hematologic malignancy were selected to be analyzed. Comorbidities and test results were collected to determine the HCT-CI score and other clinical data collected included disease and remission status at time of transplant. Results85 patients aged >55 years old who received a RIC HSCT for hematologic malignancies between January 2005 to December 2010 were analyzed. The median patient age at the time of transplantation was 63 years (range: 55-75 years). The patient diagnoses included AML (39%), NHL (29%), MM (9%), MDS (11%), CLL (8%), ALL (4%). The median pre-transplantation HSCT-CI score was 2 (range: 0-9). Among 85 patients, OS at 2 years was 44%. The 2 yr OS was 31%, 37% and 44% in the low-, intermediate-, and high-risk HSCT-CI groups (p = 0.61), respectively. The corresponding NRM at 2 years was 25%, 17% and 18% (p = 0.91). We found no predictive value of HSCT-CI for either OS or NRM in older patients having an allogeneic HSCT with reduced-intensity condition. Stratification of age (55-59, 60-64, and 65+) showed no significant impact on 2 yr OS or NRM. However, there was a trend towards a better 2 yr OS for patients who had achieved a CR versus no CR at time of transplant (48% vs 41%). ConclusionOlder patients with hematologic malignancies represent a highly selected cohort, with the prospect of an allogeneic HSCT often considered too high-risk. A method to reliably stratify these older HSCT candidates is greatly needed. However, the HCT-CI score in this retrospective analysis did not help predict their NRM or 2 year OS for patients 55 years and older with hematologic malignancies receiving a reduced intensity HSCT. Further research is warranted into what combination of factors may provide a reliable predictive score for older patients with hematologic malignancies. Disclosures:Mehta:Millennium: Speakers Bureau; Celgene: Speakers Bureau.

Hematopoietic Stem Cell Transplantation for Children with Neurological Diseases Improves the Outcomes and Not Leads to Significant Late Effects — Report from Russian Group

Strong evidence of safety, tolerability, efficacy and low rate of late effects presence after hematopoietic stem cell transplantation (HSCT) required for children with severe refractory cases of neurological diseases.We aimed to analyze the effectiveness of both allogenic and autologous hematopoietic stem cell transplantation for all cohorts of patients with neurological diseases based on safety, tolerability and late effects rate.Sixty three patients enrolled to the analysis transplanted 2004 - 2017. Diagnosis: Hurler syndrome (HS) - 40 patients, multiple sclerosis (MS) - 13 patients, metochromatic leukodystrophy (ML) - 4 patients, neuromyelitis optica (NMO) - 3 patients. Median of age 11,8 years old (3 months - 17,4 years old). Most of the patients were girls (n=39, 61,8%). All patients were with confirmed diagnosis by clinical and laboratory testing, imagining. Patients with autoimmune disorders (AD) were treated with different immunosuppressive drugs without effect. MS patients received autologous hematopoietic stem cell transplantation (HSCT) with peripheral blood stem cells (PBSC), other patients - allogenic HSCT both from related and unrelated donors. For allogenic HSCT bone marrow (BM) was used in 32 cases, PBSC - in 13 and cord blood (CB) - in 2 cases (for HS only). In 34 cases HSCT from unrelated donor were done. MS patients received Cyclophosphamide and ATG based chemotherapy before autologous HSCT, NMO and ML patients received Treosulfan, Fludarabine, Rituximab and ATG (if unrelated donor). In case of HS myeloablative conditioning (MAC) regimen was used for 29 patients and reduced intensity conditioning (RIC) - for 11 patients. RIC: Fludarabine, Melphalan, ATG. MAC: Busulfan/Treosulfan, Fludarabine, Thiotepa/Melphalan and ATG with Rituximab (in case of unrelated donors). Patients received CsA/Tacro-based with MMF/MTX GvHD prophylaxis for all allogenic cases. In 3 RIC HSCT for HS immunomagnetic СD3/СD19+ depletion of PBSC was used.All MS patients improved fast. Median follow-up of MS pts. 48,7±2,4 months (10-84 months). Two MS patients relapsed (clinical and MRI). Median of engraftment day - +10. No severe complications registered. All patients after allogenic HSCT engrafted (full donor chimerism on day +30). Median of engraftment day - 21 (11-30 days). Thirty nine patients after allogenic HSCT survived. Reasons of death: infections - 4 pts., TRALI - 1 pt., aGvHD - 1 pt. TRM improved, over the years, with improving of supportive care and donor selection as well as pre-transplant screening. No early severe toxicity revealed. GvHD: grade II - 17 patients, grade III-IV - 3 patients, local cGVHD - 3 patients. No patients had extensive cGvHD. All 5 rejected patients were with HS (MAC and RIC rejection rate was same). At median follow up of 60 months (8-160 months), the estimated probability of 5 years OS is 87%. All patients with complete donor's chimerism have good neurological response (best response correlated with early HSCT for all patients). Better status before HSCT correlated with better outcome. Cardio-vascular effects (EF decreasing) were most common for MS patients (n=7), progressive skeletal deformation - for HS patients (totally 17 cases), in one of them operative reconstitution was performed, endocrine (thyroid dysfunction, growth hormone deficiency) - for MS, NMO and HS patients (n=8), late immune reconstitution - for 1 case (NMO patient). Median period of late effects arising after HSCT was 21 month (12-27 months). All survived patients (MS, HS, ML, NMO) improved deficit in neurocognitive sphere in different grade but needed in special rehabilitation.Thus, this is the first analysis of outcomes and late effects of a group of children received HSCT for neurological diseases, especially for AD. HSCT is successful approach for patients with such diseases. In-time HSCT can significantly improve the outcome. Most of the patients remain in remission during the long time of follow-up. Long-time follow-up showed that these patients require the special observational protocol including estimation of cardio-vascular, skeletal, endocrine and neurocognitive risks. Better neurocognitive response correlated with intensive rehabilitation using computer model. Russian Joint study showed effective cooperation for treatment of such patients in the national setting. DisclosuresNo relevant conflicts of interest to declare.

AML SCT-BFM 2007: Results of the Prospective Hematopoietic Stem Cell Transplantation (HCT) Trial of the Berlin-Frankfurt-Münster (BFM) Study Group for Children with Very High Risk Acute Myeloid Leukemia

BACKGROUNDPediatric AML represents a rare and heterogeneous disease. Within the BFM study group, HCT for this patient cohort was performed with considerable inter-center variability. AML SCT-BFM 2007 was based on a transplantation consensus and aimed to prospectively generate a reliable body of data on which further transplantation technologies could be based. METHODSAML SCT-BFM 2007 was conducted according to current legislation as an international multicenter clinical trial (EudraCT: 2007-004517-34, NCT00606723), data were collected via a specifically developed remote data entry (RDE)-based data bank, and verified against source data by an on-site monitoring program. Children with cytogentic and molecular high-risk features achieving a complete first remission (CR1) and those in CR2 after a first relapse qualified for HCT from a matched donor (MD). A MD was defined to be identical when at least 9/10 alleles on the HLA-A, B, C, DRB1 and DQ loci did match. A myeloablative conditioning regimen consisting of Busulfan (age adjusted i.v. dosing: 3.2 - 4,8 mg/kg BW on days -7 through -4), Cyclophosphamide (60mg/kg iv on days -3 and -2), and Melphalan (140 mg/m2 on day -1) termed BuCyMel was used. For GVHD prophylaxis CSA and short term MTX were given, for unrelated donors anti-thymocyte globulin (ATG Neovii) was added. Children with refractory primary disease or refractory relapse were eligible for early transplantation. A cytoreductive regimen containing Fludarabine (30mg/m2/d i.v.), Amsacrine (100 mg/m2/d i.v.) and Cytarabine (2g/m2/d i.v.) all on days -12 through -9 (FLAMSA) was immediately followed by a reduced intensity conditioning (RIC) consisting of 4 Gy TBI and Cyclophosphamide (60 (unrelated)/40 (related) mg/kg/d i.v.) on days -4 and -3. After early taper of immunosuppression (MMF halted by day 40 and CSA after taper by day 90) increasing doses of prophylactic donor lymphocyte infusions (DLI) were given on days 120, 150, and 180. Standard statistical methods were used for the analysis of event-free survival (EFS, events: relapse, death from any cause), overall survival (OS), cumulative incidence of treatment related mortality (TRM) and relapse (CIR) after HCT. RESULTSRecruitment was conducted between 5/2010 and 2/2016. 97 children underwent HCT after conditioning with BuCyMel. Median neutrophil engraftment was achieved after 21 days (range 9-38). 3-year EFS and OS were 62%, standard error (SE) 5%, and 73%, SE 5%. CIR was 22%, SE 4%. Median time to relapse was 8 months (range 1-66) after HCT. TRM was 15%, SE 4%, with 8/15 patients dying before day 100. TRM correlated with age with a rate of 9% in children younger than 12 years (n = 68) and 31% in older children and adolescents (Fig. A). This resulted in a stop of using BuCyMel for older children and adolescents in 6/2014. The rate of acute graft versus host disease (aGVHD) grade II-IV was 22%, chronic GVHD developed in 11%. Median neutrophil engraftment for children transplanted for refractory disease (n= 35) was 23 days (range 10-34). 3-year EFS and OS were 46%, SE 8%, and 51%, SE 9%. EFS for primarily refractory disease was 53%, SE 11%, whereas EFS for refractory relapses (n = 7) was 29%. Relapse rate was 43%, SE 9%, and TRM reached 11%, SE 5% (Fig. B). Acute and chronic GVHD rates were at 26% and 17%. CONCLUSIONWithin a well-defined trial concept HCT from a matched donor using BuCyMel for conditioning results in an EFS of 60% with a low TRM rate in younger children. The identical approach is associated with a high TRM rate of 31% in older children and adolescents. Whether the use of alternative conditioning strategies in this population can reduce mortality while maintaining the relapse-free survival rates remains to be determined. In high-risk patients with refractory disease, early use of RIC HCT followed by the infusion of prophylactically given DLI can induce long-term remissions in more than 50% of children without increasing the risk for GVHD. [Display omitted] DisclosuresSauer:Neovii: Research Funding. Lang:Miltenyi Biotec GmbH: Patents & Royalties, Research Funding. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Handgretinger:Miltenyibiotec GmbH: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.

Incidence, Predictors, and Outcomes of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation.

fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P=.006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P=.0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P=.06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P=.002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P < .001) or other (HR, 32; 95% CI, 3.9 to 257; P=.001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.

Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Sickle Cell Disease.

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and early mortality. Acute and chronic SCD-related complications increase with older age, and therapies are urgently needed to treat adults. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but has been used less frequently in adults compared to children. This is, in part, due to (1) greater chronic organ damage, limiting tolerability to myeloablative conditioning regimens, (2) a higher rate of HSCT-related complications in adults versus children with SCD, and (3) limited coverage by public and private health insurance. Newer approaches using nonmyeloablative and reduced-intensity conditioning HSCT regimens have demonstrated better safety and tolerability, with high rates of stable engraftment in SCD adults. This review will focus on the impacts of HSCT, using more contemporary approaches to SCD-related complications in adults.

Hematopoietic stem cell transplantation in a patient with type 1 mosaic variegated aneuploidy syndrome

BackgroundMosaic variegated aneuploidy (MVA) syndrome is a chromosomal instability disorder that leads to aneuploidies of different chromosomes in various tissues. Type 1 MVA (MVA1) is caused by mutations in the budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) gene. The main clinical features of MVA1 syndrome are growth and mental retardation, central nervous system anomalies, microcephaly, and predisposition to cancers. There have been no reports of hematopoietic stem cell transplantation (HSCT) in MVA patients.ResultsWe report an 11-year old boy diagnosed with MVA1 syndrome. The BUB1B gene mutations c.498_505delAAACTTTA and c.1288 + 5G > A were detected using the next generation sequencing (NGS) method. The patient presented with cytopenia soon after birth, but remained stable until 9 years of age, when he developed myelodysplastic syndrome associated with monosomy of chromosome 7. Due to severe dependence on blood transfusions, a TCRαβ+/CD19+ depleted HSCT was performed from a matched unrelated donor (MUD) using a treosulfan-based reduced intensity conditioning (RIC) regimen. The engraftment occurred, and no severe toxicity was observed soon after the HSCT, but on day + 47, graft rejection was detected. It was followed by prolonged pancytopenia and sepsis with multi-organ Enterococcus faecium infection, which led to the patient’s death on day + 156 after HSCT.ConclusionsIn conclusion, we demonstrate that RIC HSCT with TCRαβ+/CD19+ depletion was well tolerated and resulted in complete hematologic recovery in our MVA1 patient, but, unfortunately, it was followed by rapid graft rejection. This fact needs to be taken into consideration for HSCT in other MVA patients.

Chronic Cholangiopathy Associated with Primary Immune Deficiencies Can Be Resolved by Effective Hematopoietic Stem Cell Transplantation

To investigate effects and outcome of hematopoietic stem cell transplantation (HSCT) on sclerosing cholangitis, in pediatric patients with different primary immunodeficiencies (PIDs). From databases in 2 tertiary centers for immunodeficiencies and liver disease, we have identified children with PIDs and sclerosing cholangitis, who have paired clinical, radiologic, and histologic information before and after HSCT and studied their clinical progress and outcome. Seven of 13 children (53.8%) died at a median interval of 4months (range, 3 months-5 years) after HSCT. However, 6 surviving children (46.2%) with different PIDs and less severe cholangiopathies showed an improvement in markers of liver injury within months of successful unrelated reduced intensity conditioning HSCT. The repeated native liver biopsy, performed in 4 patients at a median of 96 (range, 4-144) months post-HSCT, showed a considerable improvement. Biochemical markers of liver function in the survivors completely normalized after a median of 13months (range, 2-48). All patients continue to have a mildly dilated extrahepatic biliary system on ultrasonography with no intrahepatic ductal changes on magnetic resonance cholangiography after a follow-up of median 18years (range, 2-20). Effective HSCT has the potential to improve biochemical and histologic features of cholangiopathy in children with PIDs, presumably by clearance of chronic infection following establishment of immune competence. However, careful patient selection is critical as advanced liver injury is often associated with serious complications and mortality.

Genetic Predispositions, Management Strategies, and Clinical Outcomes in Adults with Hemophagocytic Lymphohistiocytosis (HLH) after Reduced-Intensity Conditioning (RIC) Hematopoietic Stem Cell Transplantation (HSCT) at Dana-Farber Cancer Institute

Introduction HLH has historically been considered a pediatric disease. There are limited prospective data for adults with HLH, particularly on management during and outcomes after allogeneic HSCT. Following the CTN1204 study of HSCT in pediatric HLH, this retrospective analysis sets a benchmark for adult-onset HLH. Subjects We identified 20 patients, median 45yo (21-72), who underwent RIC HSCT for HLH since 2010. 5 (25%) had a malignancy, 3 (15%) a rheumatologic diagnosis, and 3 (15%) a viral precipitant. Of 17 patients tested, 65% had ≥1 variant in HLH-associated or immunologically-relevant genes. (Table) Initial therapy was largely etoposide/dexamethasone (n=16) or malignancy-directed chemotherapy (n=5), with multiple agents, including alemtuzumab, as salvage/bridging therapy. (Figure 1) 17 patients received alemtuzumab as “pre-conditioning” for HSCT, intentionally stopped median 25 days (19-32) prior to cell infusion. Conditioning was fludarabine/busulfan (n=17) in 7 related and 11 unrelated HSCTs or fludarabine/cyclophosphamide/TBI in 2 haploidentical HSCTs. 50% received PBSCs. HSCT occurred median 8 mos after HLH diagnosis (3-13). Results All patients engrafted neutrophils (median 15.5 days) and platelets (median 19.5 days). Donor leukocyte and T-cell chimerisms were variable (30day 43-100%, 5-100%; 1 yr 67-100%, 40-100%). 2 patients received CD34-selected infusions for cytopenias with full donor chimerism; 2 had DLIs for T-cell chimerism ≤20% to augment sustained remission. There was no correlation between alemtuzumab timing and chimerism. With follow-up of 22 months (3-61), 6mo Grade II-IV acute GvHD was 17%, and 12mo cGvHD was 35%. 2 patients relapsed with DLBCL at 3-4 mos; 1 with concurrent HLH. There were no isolated HLH relapses. Before HSCT, patients experienced 7 viral, 8 bacterial, and 5 fungal infections, plus 3 surgeries. In the year following HSCT, 3 patients had CMV, 1 adenoviral, 1 fungal, and 7 bacterial infections. 3 patients required steroids for hyperinflammatory pulmonary syndromes. 18mo OS was 83% (95% CI, 56-94) which compares favorably with 80% OS on CTN1204 and 57-60% on prior CIBMTR query of HSCT in adults with histiocytic diseases. (Figure 2) (Nikiforow. Tandem Mtg 2014). Conclusions Variants in genes associated with familial HLH and other syndromes of immune dysregulation (e.g., Chediak Higashi, Familial Mediterranean Fever) reflect a significant and under-appreciated predisposition to adult-onset HLH. Infectious complications and need for 2nd cell therapies occur, but overall, RIC HSCT preceded by alemtuzumab therapy is a highly feasible approach in adults.

Incidence and Predictors of Hepatic Veno-Occlusive Disease after Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Hepatic veno-occlusive disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT) that is triggered, at least in part, by conditioning regimen-induced sinusoidal endothelial cell injury. VOD is thus commonly, but not exclusively, associated with myeloablative conditioning (MAC). The incidence of VOD in reduced intensity conditioning (RIC) HSCT was ≈2% in a single center series (Carreras et al. BBMT 2011), and risk factors for VOD in RIC HSCT remain poorly defined. Methods: We performed a retrospective review to confirm all cases of VOD among patients undergoing RIC HSCT at the Dana-Farber Cancer Institute/Brigham and Women9s Cancer Center between January 2007 and June 2017. Diagnosis of VOD was based on modified Seattle or Baltimore criteria and/or liver biopsy or RUQ ultrasound in conjunction with fluid retention/ascites and hepatomegaly/RUQ pain. Diagnosis dates for all VOD cases were confirmed and clinico-laboratory values collected in the 10 days preceding the diagnosis. The same data were collected for a randomly selected control non-VOD RIC cohort, calculated from the median day of VOD onset derived from the cases. Acute kidney injury was defined as an absolute increase in creatine by 0.3 mg/dL or a relative increase of > 50% within a 48-hour period. Increased platelet transfusion requirement was defined as requiring a platelet transfusion on 2 consecutive days in the 7 days prior to VOD diagnosis, excluding transfusions for procedures. Incidence of VOD at D50 was calculated using a competing risk framework. Cox regression was used to identify significant features for predicting VOD. Survival was compared to a concurrent cohort of 76 patients with VOD after MAC HSCT recently published from our center (Roeker et al. BBMT 2018). Results: A total of 1492 patients underwent RIC HSCT, of whom 1070 (67.8%) received sirolimus (Sir) with tacrolimus (Tac) as part of the GVHD prophylaxis, and 1217 (82%) received intravenous busulfan(Bu) 3.2 or 6.4mg/kg with fludarabine(Flu) as conditioning. Twenty-six developed VOD (median day of diagnosis = d+26, range 5-48 days), for a cumulative incidence of 1.6% (95%CI 1.1%-2.4%). The median bilirubin at diagnosis was 1.1 mg/dL(range 0.6-5.2). Only 5 (19.2%) patients had a bilirubin of ≥2.0 mg/dL on the date of VOD diagnosis, although total bilirubin peaked at ≥ 2 mg/dL in 17 of 26 (65.4%). VOD was mild/moderate in 16 and severe in 10 patients. Sixteen had received ursodiol as VOD prophylaxis. Defibrotide was used as treatment in 17 cases. The 2-year overall survival (OS) was 54% from VOD onset. VOD was associated with increased risk for NRM (HR 4.02, 95% CI 2.1-7.7, p 1, increasing platelet transfusion requirements, and increasing Tac and Sir trough levels (Table 1, Fig 1). Conclusions: The incidence of VOD in this large modern cohort of 1492 RIC HSCT patients was 1.6%, and was associated with the use of Sir with Tac. Onset of VOD in RIC patients was delayed (median D+26 vs. D+14) and 2 yr-OS is superior compared to MAC patients. Only 19% of the RIC VOD cases met the bilirubin threshold for Baltimore and Seattle criteria at diagnosis, suggesting that the rise in bilirubin is a later event in these RIC VOD cases, whereas increasing platelet transfusion requirements, sudden rise in Tac and Sir levels, elevated serum creatinine and acute renal injury appear to be early clinical predictors. Disclosures Nikiforow:Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees; Amgen: Membership on an entity9s Board of Directors or advisory committees; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Ho:Jazz Pharmaceuticals: Consultancy.

Hematopoietic Stem Cell Transplantation in Children with Refractory Acute Lymphoblastic Leukemia

▪PurposeIt is difficult to decide whether children with leukemia who could not achieve complete remission (CR) after relapse or primary induction failure should undergo transplantation. Nonetheless, allogeneic hematopoietic stem cell transplantation (HSCT) is a possible approach for refractory acute leukemia including acute lymphoblastic leukemia (ALL). Even after refractory to conventional chemotherapy, a graft versus leukemia (GVL) effect could be expected to some extent. This approach is considered to be experimental because the mortality rate of HSCT is extremely high. A previously conducted large-scale study showed that age younger than 10 years was a factor of good prognosis; however, the details in children are unclear. The purpose of this retrospective analysis was to describe the outcomes and risk factors of HSCT for children with refractory ALL.Patients and MethodsThe data was collected through the Transplant Registry Unified Management Program (TRUMP) system, the registry of The Japan Society for Hematopoietic Cell Transplantation. In total, 325 patients with ALL younger than 21 years old when HSCT was performed between January 2001 and December 2015 and who harbored blasts in peripheral blood and/or bone marrow were analyzed. Both myeloablative regimens and reduced-intensity conditioning regimens were analyzed. Patients were classified as having poor-risk cytogenetics with either t(4;11), t(9;22), t(8;14), hypodiploidy or near triploidy, or more than 5 cytogenetic abnormalities. Other ALL cytogenetic findings were classified as other abnormalities or normal. Myeloablative conditioning was defined as total body irradiation (TBI) of >8 Gy and the administration of 8 mg/kg of busulfan (BU), >140 mg/m2 of melphalan, or >10 mg/kg of thiotepa. All other regimens were analyzed as reduced-intensity conditioning HSCT, including low-dose TBI (≤8 Gy) and low-dose BU (≤8 mg/kg). The graft included bone marrow, peripheral blood stem cells, or cord blood. Overall survival (OS) was used as a primary outcome because for HSCT during relapse, post-HSCT CR was not always achieved or reliably documented.ResultsThe median follow-up time of survivors was 1145 days (range 110-3710). The median age was 11 years. Thirty-five percent of patients had a pre-HSCT performance status (PS) of 0, which corresponds to a Karnofsky PS of ≥90. The rate of pre-HSCT fungal infection was 14%. Fifty-nine patients had more than 25% marrow blasts when HSCT was performed. When HSCT was performed, 10%, 60%, and 30% of patients exhibited primary induction failure, first relapse, and second or later relapse, respectively. Ninety-one percent of patients had neutrophils and 67% exhibited platelet recovery by day 100. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) on day 100 was 43%. The cumulative incidence of chronic GVHD (cGVHD) at 3 years after HSCT was 19%. Two hundred and forty-seven patients died. The causes of death were leukemia progression (57%), followed by graft failure (11%), GVHD (10%), hemorrhage (6%), and infection (5%). The 3-year OS rate in all the patients was 22% (95% confidence interval (CI), 18-27). Age, white blood cell count at diagnosis, prior history of central nervous disease, disease status, conditioning regimens, donor-recipient human leukocyte antigen match, graft type, or year in which HSCT was performed did not affect the OS. Grade ≥2 aGVHD did not affect OS. Whereas Patients with chronic GVHD had better 3-year OS (49%, 95% CI 35-61%) compared to that in patients without chronic GVHD (22%, 95% CI 16-29%) (p = 0.001) (Figure 1). Multivariate analysis showed that other than cGVHD, low PS (relative risk (RR): 2.53), blasts in bone marrow greater than 25% (RR: 1.43), T cell phenotype (RR: 1.86), high-risk or normal cytogenetics (RR: 1.42), and a history of HSCT (RR: 1.90) were significant adverse pre-HSCT variables (Table 1). Patients who had 0 or 1 (n = 113), 2 (n = 113), and 3-5 pre-HSCT variables (n = 99) had 42% (95% CI, 32-51), 17% (95% CI, 10-25), and 6% (95% CI, 2-13) 3-year OS, respectively (Figure 2).ConclusionSome patients with refractory pediatric ALL achieved relatively long survival following HSCT in the relapsed period, especially when a GVL effect was obtained. A scoring system using pre-HSCT variables should help decide whether HSCT should be performed or not. HSCT is worth considering for children who have undergone ≤2 pre-HSCTs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic Stem-Cell Transplantation in Children with Refractory Acute Myeloid Leukemia

PurposeIt is difficult to decide whether children with leukemia who could not achieve complete remission (CR) after relapse or primary induction failure should undergo transplantation. Nonetheless, allogeneic hematopoietic stem cell transplantation (HSCT) is a possible approach for refractory acute myeloid leukemia (AML). Despite being refractory to conventional chemotherapy, a graft versus leukemia (GVL) effect could be expected to some extent. This approach is considered to be experimental because the mortality rate of HSCT is extremely high. A previously conducted large-scale study demonstrated that age less than 10 years was a factor of good prognosis; however, the details in children remain unclear. The purpose of this retrospective analysis was to describe the outcomes and risk factors of HSCT for children with refractory AML.Patients and MethodsThe data was collected through the Transplant Registry Unified Management Program (TRUMP) system, the registry of The Japan Society for Hematopoietic Cell Transplantation. A total of 417 patients with AML younger than 21 years old at the time of HSCT between January 2001 and December 2015 who had blasts in peripheral blood and/or bone marrow were analyzed. Both myeloablative and reduced-intensity conditioning regimens were analyzed. Patients with AML were classified according to a previous report, which was based on the Eastern Cooperative Oncology Group/Southwest Oncology Group classification as good (inv16, t[8;21], t[15;17]), poor (5/del[5q], 7/del[7q], inv[3q], abn11q, 20q or 21q, del[9q], t[6;9], t[9;22], abn17p, and complex karyotype defined as 3 or more abnormalities), or intermediate (other and normal karyotypes) risk. Myeloablative conditioning was defined as total body irradiation (TBI) of >8 Gy and the administration of 8 mg/kg of busulfan (BU), >140 mg/m2 of melphalan, or >10 mg/kg of thiotepa. All other regimens were analyzed as reduced-intensity conditioning HSCT, including low-dose TBI (≤8 Gy) and low-dose BU (≤8 mg/kg). The graft included bone marrow, peripheral blood stem cells, or cord blood. Overall survival (OS) was used as a primary outcome because for HSCT during relapse, post-HSCT CR was not always achieved or reliably documented.ResultsThe median follow-up time of survivors was 1052 days (range 60-4399). The median age was 13 years. Twenty-three percent of patients had a pre-HSCT performance status (PS) of 0, which corresponds to a Karnofsky PS ≥90. The rate of pre-HSCT fungal infection was 12%. Fifty-two percent of patients had more than 25% marrow blasts at the time of HSCT. At the time of HSCT, 36%, 47%, and 17% of patients exhibited primary induction failure, first relapse, and second or additional relapse, respectively. Eighty-nine percent of patients had neutrophils and 70% exhibited platelet recovery by day 100. Three hundred and fourteen patients died. The causes of death were leukemia progression (58%), followed by graft-versus-host disease (GVHD) (11%) and graft failure (10%). The 3-year OS rate was 23% (95% confidence interval (CI) 19-28). Grade ≥2 acute GVHD did not affect OS. Patients with chronic GVHD had better 3-year OS (47%, 95% CI 36-57%) compared to that in patients without chronic GVHD (22%, 95% CI 16-28%) (p = 0.001) (Figure 1). Low PS, greater than 25% marrow blasts, the presence of blasts in blood at the time of transplantation, French-American-British subgroup other than M1 or M2, transplant from a male donor, and a history of transplantation were adverse pre-HSCT variables (Table 1). Patients with 0 (n = 24), 1-2 (n = 175), 3-4 (n = 188), and 5-6 (n = 30) variables had 52% (95% CI 30-71%), 30% (95% CI 23-37%), 17% (95% CI 12-23%), and 0% 3-year OS, respectively (p < 0.001) (Figure 2).DiscussionSome patients with refractory pediatric AML achieved relatively long survival following HSCT in the relapsed period, especially when a GVL effect was obtained. A scoring system using pre-HSCT variables should help decide whether HSCT should be performed or not. HSCT is worth considering for children who have undergone ≤2 pre-HSCTs. DisclosuresNo relevant conflicts of interest to declare.

Reduced Fertility Potential in Young Patients Following Hematopoietic Stem Cell Transplantation Despite Reduced Intensity Conditioning

Reduced intensity conditioning (RIC) is increasingly used for hematopoietic stem cell transplantation (HCT). Risk of infertility and primary gonadal insufficiency secondary to standard myeloablative (MAC) HCT is high, but little is known of these complications following use of RIC HCT.

Post-Transplant CD34+ Selected Stem Cell “Boost” for Mixed Chimerism after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation in Children and Young Adults with Primary Immune Deficiencies

Mixed chimerism and eventual graft loss occurs in a proportion of children with primary immune deficiencies receiving alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens before allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the usefulness of a CD34+ selected stem cell “boost” without conditioning to treat mixed chimerism in children and young adults who received predominantly an alemtuzumab, fludarabine, and melphalan RIC regimen for primary immune deficiencies and reported the outcomes. Patients with a primary immune deficiency disorder who were either enrolled on a prospective CD34+ boost study for treatment of mixed chimerism from 2011 to 2014 (n = 9) or treated with a CD34+ boost on a clinical basis from 2014 to 2016 (n = 3) were included in this analysis. Response to a CD34+ boost was defined as a rise in donor chimerism by ≥15% with donor chimerism of at least 20%, stabilization was defined as a rise in chimerism by <15% with donor chimerism ≥ 20%, and no response was defined as any decline in donor chimerism or need for a second HSCT after a CD34+ boost. Twelve patients received alemtuzumab, fludarabine, and melphalan. Median age was 4.5 years (range, .9 to 20.6), and median whole blood donor chimerism before the boost was 25% (range, 3% to 61%). Three patients (25%) met criteria for response, 1 patient (8%) was considered to have stabilization, and 8 patients (67%) had no response 12 months after the boost. None of the patients developed any complications from a CD34+ boost, including no acute graft-versus-host disease (GVHD). All patients are alive with a median follow-up of 32 months (range, 8 to 79). We conclude that a CD34+ selected stem cell boost can be considered for treatment of mixed chimerism after alemtuzumab, fludarabine, and melphalan RIC HSCT in children and young adults with primary immune deficiencies. Approximately one-third of patients can be expected to benefit from a CD34+ selected stem cell boost and may avoid the need for a second HSCT. Lack of any GVHD or toxicity makes a stem cell boost an attractive option compared with donor lymphocyte infusions for treatment of mixed chimerism.

Higher Donor Apheresis Blood Volumes Are Associated with Reduced Relapse Risk and Improved Survival in Reduced-Intensity Allogeneic Transplantations with Unrelated Donors

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume ≥15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT.