CD34 Cell Dose Research Articles

Early Infectious Complications after Autologous Hematopoietic Cell Transplantation (AHCT) for Lymphoma

The spectrum of infectious complications occurring in the first 100 days in lymphoma patients undergoing AHCT has not been well described in the contemporary era of improved supportive care practices and antimicrobial prophylaxis.We conducted a retrospective cohort study to describe early infections in this population and to evaluate the association of early infections with long-term outcomes. From our BMT Program database, we identified 544 consecutive patients (age ≥18 years) who received their first AHCT for lymphoma between 2007 and 2016 and had consented for use of their data for research. Median age was 55 (range, 19-78) years, 63% patients were male, 79% had non-Hodgkin lymphoma (NHL), 96% had KPS ≥80, 39% had AHCT Comorbidity Index score ≥3, and 78% had intermediate/high risk disease. Stem cell mobilization was performed with chemotherapy priming (58%) or G-CSF ± plerixafor (42%). The majority of patients received conditioning regimen consisting of busulfan, cyclophosphamide and etoposide (97%). All patients were hospitalized from start of conditioning chemotherapy until neutrophil engraftment. Routine antimicrobial prophylaxis consisted of ciprofloxacin and fluconazole starting on hospitalization and continued until neutrophil engraftment, and acyclovir for 6 months after transplantation.The following infections were evaluated: all (excluding febrile neutropenia [FN]), bacterial, viral, fungal, C difficile, central line associated blood stream infection (CLABSI), blood stream, pneumonia, and other sites, and FN. Compared to patients without infections, those who had early infections were older (median 57 vs 55 years, P=0.04), more likely to have NHL (86% vs 77%, P=0.04), and had earlier stage disease (P<0.01); there was no difference in the CD34 cell dose or time to neutrophil engraftment. Cumulative incidence of all infections at 100 days (excluding FN) was 19.1% and that of FN was 77.4% (Table). Among bacterial infection episodes (N=114), E coli(18%), C difficile(15%), and S aureus(9%) were the most common organisms identified; the majority of viral infection episodes were caused by respiratory viruses (62%). Compared to no infections, patients with infections had a significantly longer transplant hospitalization and more readmissions, and fewer days alive and out of hospital in first 100 days; there was no difference in 100 day overall mortality between the two groups (3.2% vs 4.8%, P=0.42). In multivariable analyses, older age at AHCT was the only risk factor for any infection (excluding FN; HR 1.21 per 10 year increase, 95% cumulative incidence 1.06-1.39, P=0.006); no association was observed with other risk factors examined, including KPS score, comorbidities, prior therapy, disease risk or time since diagnosis. Disease risk was the only factor independently predictive of FN; compared to low risk disease, patients with intermediate risk (HR 0.78, P=0.01) and high risk (HR 0.71, P=0.05) disease had lower risks of FN. Older age was the only risk factor for C difficilecolitis (HR 2.19 per 10 year increase, P<0.001), while risks for CLABSI increased over time (HR 1.41 per 1 year increase, P=0.002). In a landmark analysis including 100 day survivors (N=525 patients), patients with infections within the first 100 days had higher CI of 1-year non-relapse mortality (4% vs. 1% for no infections, P=0.02) and lower 1-year overall survival (81% vs. 90%, P<0.001), which was confirmed on multivariable analyses (HR 1.92, P=0.02 for non-relapse mortality, HR 1.80, P<0.001 for overall mortality). Although representative of our institutional practices, our study describes the spectrum and incidence of early infectious complications after AHCT for lymphoma in the current era. Early infections are relatively common, impact long-term survival, and have significant resource implications. Notwithstanding advances in supportive care, continued focus in this area is needed to improve outcomes in this population. DisclosuresHill:Amgen: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Majhail:Atara: Honoraria; Anthem, Inc.: Consultancy; Incyte: Honoraria.

Comparable Outcomes after Hematopoietic Stem Cell Transplantation from Mother Donors and Matched Unrelated Donors in Patients with Hematopoietic Malignancies

BACKGROUND Haploidentical donor (HID) transplantations have achieved comparable survival as HLA fully matched unrelated donor (URD) transplantations. However, previous studies usually consider the two donor sources as whole populations when making the comparison, although there are actually subgroups within each. Based on current knowledge regarding donor selection, offspring and sibling donors were prioritized over parental donors in unmanipulated haplo-transplant settings, and maternal donors were considered as “the worst donors” under the Beijing Protocol due to the increased probabilities of GVHD and inferior survival. To compare efficacies of “the worst” mother donors and URDs would help to acquire a further understanding on donor selection of HIDs versus URDs.PATIENTS AND METHODS 43 and 92 patients who underwent transplantations with URDs or mother donors from June 2012 to June 2015 were enrolled. Their transplantation outcomes, including hematopoietic recovery, acute and chronic GVHD, relapse, transplant related mortality (TRM), overall survival (OS) and leukemia-free survival (LFS) were compared. Univariate and multivariate analysis were performed to explore risk factors for transplantation outcomes.RESULTS Both 2-year OS and 2-year LFS were comparable between the mother donor group and the URD group (74.8% versus 72.9%, p=0.937 and 71.7% versus 67.0%, p=0.580). Higher incidences of grade 2 to 4 acute GVHD and chronic GVHD were observed in the mother donor group than that in the URD group (43.5% versus 14.0%, p=0.001 and 58.8% versus 37.1%, p=0.013), although incidences of grade 3 to 4 aGVHD were similar between groups (mother donor group: 12%, URD group: 7%, p=0.374). Multivariate analysis indicated increased rates of acute GVHD were associated with mother donor transplantations (HR ratio: 2.049, p=0.017) and chronic GVHD was related to lower dose of CD34 cells infused (HR ration: 1.834, p=0.035) and female to male donations (HR ration: 1.733, p=0.047). The 2-year cumulative incidences of relapse were significantly decreased in the mother-donor group (7.6% versus 20.9%, p=0.036). Incidences of relapse were associated with donor types (URD vs mother donor: HR ratio 2.524, p=0.035) and disease status before transplantation (CR1 vs other: HR ratio 0.201, p=0.001) in multivariate analysis. These two groups were comparable in hematopoietic recovery and TRM (mother donor group: 21.1%, URD group: 11.6%, p=0.173).CONCLUSIONS Our findings suggest that mother donor transplantations could achieve comparable survival to unrelated donor transplantations, and exhibited decreased rates of relapse but increased rates of GVHD under the Beijing Protocol. This study not only shed light on donor selection by using one modality (the Beijing Protocol) to answer the universal question of HIDs versus URDs, but was also of practical significance due to possible shortage of unrelated donors, sibling donors and other suitable HIDs, especially in contemporary China with the one family one kid policy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cord Blood Transplants Supported By Unrelated Donor CD34 Progenitor Cells

Abstract Introduction: Umbilical cord blood (UCB) transplant supported by third party CD34-selected cells results in rapid count recovery, UCB mediated GVL effects and low rates of chronic GvHD. For patients lacking haplo-identical relatives, other sources of CD34 progenitors are needed. Methods: We identified partially matched unrelated donors for patients lacking suitable haplo-identical donors -including second-degree relatives - and who otherwise were candidates for haplo-cord transplant. Most were treated on prospective studies (clinicaltrials.gov 00943800 and 01810588). For 5 patients, UCB were obtained through NCT01351545. Results: Between 12/2014 to 7/2018 of 126 candidates for haplo-cord transplant, 26 (21%) had no suitable related donor. Most common reasons were: no first or second degree partially matched donors, ill or unavailable relative, high titers of HLA-antibodies against all relatives, or evidence of hematological familial hereditary syndrome. Diagnoses were: 16 AML/MDS, 5 ALL, 2 MPN, 1 NHL, 1 plasma cell leukemia and 1 SAA. Median age was 57 (24-75). 50% were women. 42% non-Hispanic white (NHW), 19% non-Hispanic blacks (NHB), 19% Hispanic, 8% other minorities. CIBMTR Disease Risk Index (DRI): 46% intermediate, 38% high and 8% very high. Median HCT-CI was 3.5 (25%-75% IQR 2-6). Conditioning: 16 Flu/Mel/TBI (94% 400cGray), 8 Flu/Mel,1 Flu/Cy, 1 Etoposide/TBI. All except 1 received ATG 4.5 mg/kg and all received post-transplant Tacrolimus and MMF. UCB matching was 4/8, 5/8, 6/8 or 7/8 HLA in 12%, 27%, 23%, and 38%, respectively. HLA matching for unrelated haplos was 5-6/12, 7-8/12, &gt;9/ 12 HLA in 15%, 54% and 19%, respectively. For UCB, median cells collected were 2.1 (range1.1-4.0) ×107 TNC/kg. CD34 cell dose of unrelated donor graft was 3-5 ×106 CD34/kg. Median time to ANC engraftment was 11 days (range 9-35) and platelet engraftment was 18 days (range11-124). Chimerism on day 56 are shown in figure 1. There were three patients with graft failures: Pt #5 with complete graft rejection, autologous reconstitution, but ongoing clinical remission that persists to date (Day+ 1223); Pt #13 with graft failure and subsequent relapse, rescued with second UCB HSCT but died of progression of disease; and pt #18 who died from infectious complications after graft failure. Acute GvHD occurred in 35% of patients (4 Grade I-II, 4 Grade III, and 1 Grade IV). cGvHD was rare: One patient with mild severity and a second with severe lung involvement. After a median follow up of 209 days, 6 months cumulative incidence of relapse (CIR) was 16% and non-relapse mortality (NRM) was 20%. Median OS was 14 months (95%CI 7-27). Conclusion: 20% of adults without matched related or unrelated donors, also lack suitable first or second degree haplo-identical donors. UCB transplant with partially matched unrelated donor accessory cells provides an alternative for transplantation. Engraftment is rapid, rates of acute GVHD are acceptable and incidence of chronic GVHD is very low. Prolonged survival is encouraging in this patient cohort with adverse characteristics and who would not be candidate for haplo-identical HSCT. Disclosures No relevant conflicts of interest to declare.

Impact of CD34 Cell Dose Infused on the Duration of Absolute Neutropenia after High Dose Melphalan and Autologous HCT for Myeloma

Background: High-dose melphalan with autologous stem cell transplantation (AHCT) is a key component in the treatment of patients with multiple myeloma (MM). The use of AHCT has been shown in several clinical trials to improve event-free and overall survival and is accepted as standard of care in medically fit patients. The use of high doses of melphalan is associated with a period of myelosuppression which has not been reduced despite higher doses of infused stem cells and stem cell fractionation. This period of obligate neutropenia results in significant life-threatening complications and increased financial costs. The aim of this study was to identify predictors of duration of neutropenia as a baseline to developing strategies that minimize neutropenia and thereby symptom burden after high-dose chemotherapy and AHCT.Methods: We retrospectively reviewed patients who had a diagnosis of MM and who had a first AHCT at our Institution between 1/2011 and 12/2016 with high-dose melphalan. We determined the incidence of absolute neutropenia (defined as ANC <500 cells/μL) lasting greater than 3 days. Kaplan-Meier and log-rank test was used to determine overall survival (OS) in patients with neutropenia lasting greater than 3 days or 3 days or fewer. Univariate analysis was done to determine the relative risk of absolute neutropenia greater than 3 days based on age, gender, International Staging System (ISS), cytogenetic risk category, and stem cell dose.Results: Of 434 patients, 261 (60%) developed absolute neutropenia lasting greater than 3 days (range 4-18). The median age at time of AHCT was 60 years (range) with 188 (50%) being ISS-I, 111 (29%) ISS-II, and 79 (21%) ISS-III. The majority of patients (73%) had 1 induction regimen prior to AHCT. Conditioning was melphalan 200 mg/m2 (79%), 180 mg/m2 (1%), or 140 mg/m2 (18%). The median cell dose was 5.1 x106 CD34+ cells/kg (range 1.7-16.1). Patients with absolute neutropenia lasting greater than 3 days had longer hospitalizations (p=<0.001), longer time to ANC recovery (p=<0.001), and longer time to platelet recovery (p=0.004) compared to patients who had absolute neutropenia for 3 days or less. With a median follow up of 30 months (range 3- 72), 50/434 had died for a 3-year OS of 87.8% (95% CI: 83.5- 91.0). The 3-year OS for patients who had absolute neutropenia greater than 3 days was 85.4% (95% CI: 79.3 - 89.9), compared to 91.5% (95% CI: 84.9 - 95.3) for patients who had absolute neutropenia for 3 days or fewer. There was a trend towards improved survival in patients with absolute neutropenia lasting 3 days or fewer (p=0.08). By univariate analysis, patients with ISS stage III disease had an increased risk of greater than 3 days of absolute neutropenia compared to patients with ISS stage I (RR: 1.28, 95% CI: 1.06 - 1.54; p=0.009). Patients who received fewer than 4.25 x 106 CD34+ cells/kg had an increased risk of greater than 3 days of absolute neutropenia compared to patients who received greater than 6.06 x 106 CD34+ cells/kg (RR: 1.59, 95% CI: 1.27-1.98; p<0.001).Conclusions: The incidence of obligate absolute neutropenia lasting 3 days or more was 60% in patients after high-dose melphalan AHCT and duration of neutropenia impacted post-AHCT outcomes. While there was no statistical difference in OS in patients with less or greater than 3 days of neutropenia, there was a trend towards better survival in patients with absolute neutropenia of 3 days or less. To our knowledge this is the largest series in the modern era to report on engraftment kinetics after AHCT in MM patients. Minimizing the duration of neutropenia and need for transfusion support during AHCT has the potential to improve the safety of high-dose therapy, reduce costs, and decrease transplant-related morbidity and mortality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Curative Allogeneic Stem Cell Transplantation Is Safe and Feasible in Adult Patients with Sickle Cell Disease Despite Lack of Matched Sibling Donor and Presence of Sickle Cell-Related Co-Morbidities

Introduction:Sickle cell disease (SCD) affects 300,000 annual births globally, and about 100,000 individuals in the United States. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only cure. HSCT risks necessitate a risk-benefit analysis in each case. Excellent long-term overall survival (OS) of 91-95% has been described with matched-sibling (SIB) HSCT, but fewer than 15% of SCD patients have a SIB donor. Matched unrelated donor (MUD) availability is limited for ethnic groups afflicted with SCD. Alternative donor HSCT from mismatched unrelated donors (MMUD) or haploidentical donors improves donor availability but increases toxicity and risk of graft failure. SCD-induced organ damage is another limitation to HSCT. In this study, we review our experience with HSCT for SCD and demonstrate that most patients can receive a curative HSCT despite lack of SIB donor and presence of significant co-morbidities.Methods:All adult SCD patients who received HSCT at our center since 2014 were included. Patients had at least 2 hospitalizations per year for pain crises despite hydroxyurea compliance and evidence of end-organ damage. Patients with a SIB donor (n=6) received conditioning with alemtuzumab and 3Gy TBI (per Hsieh et al, 2009). Patients with MUD/MMUD (n=4) or haploidentical (n=1) donors received conditioning with alemtuzumab, fludarabine, melphalan, and a CD34+ selected graft with CD3+ cell add back on an ongoing clinical trial for non-malignant hematologic diseases. One patient s/p kidney transplant and liver failure requiring TIPS procedure was conditioned with alemtuzumab and 4Gy TBI, received a 10/10 MUD graft, and given post-HSCT cyclophosphamide (50 mg/kg d+3) along with sirolimus continuation as GVHD prophylaxis. GVHD prophylaxis otherwise consisted of sirolimus (n=10) and tacrolimus (n=1). All patients received a G-CSF mobilized peripheral blood stem cell (PBSC) graft and underwent RBC exchange to achieve Hgb S <30%.Results:Twelve patients are included in this analysis. Median age was 28.7 (18.5 - 44.2) years with 6 males and 6 females. Median follow up was 13.6 months (range 1.4 - 51.3). Two patients had stage V renal disease with one patient on active dialysis. Two patient were s/p kidney transplant with one patient awaiting a 2nd kidney transplant. Median CD34 cell dose in SIB and MUD/MMUD HSCT was 14.8 and 8.5 x 10e6 CD34/kg respectively. Median T cell add back in CD34-selected M/MMUD recipients was 2.5 x 10e5 CD3/kg. No G-CSF was used. All patient engrafted with no cases of graft failure or treatment related mortality (TRM). Median time to neutrophil engraftment for SIB and M/MMUD recipients was 24.5 and 19 days respectively. Median time to platelet engraftment was 19 days for M/MMUD recipients and 2 of 6 SIB recipients required only 1 platelet transfusion each. The patient s/p kidney allograft and TIPS for liver failure engrafted neutrophils and platelets on day +22 and +26 respectively. All patients are alive and free of SCD. Available chimerism analysis at 6 months (n=8) shows median myeloid chimerism to be the same in SIB and M/MMUD recipients (99.7%) where median T Cell chimerism was 35% and 65% for SIB and M/MMUD recipients respectively. Chimerism at 1 year shows stable myeloid engraftment and median T cell chimerism of 61.5% for SIB recipients.Two cases of PRES were noted after HSCT, one in a patient on tacrolimus after which the CD34-selected protocol was modified to include sirolimus as GVHD prophylaxis. Another case of PRES was noted on sirolimus which was switched to prednisone and mycophenolate mofetil. Two patients discontinued sirolimus due to myalgias and were switched to tacrolimus on days +44 and +58 with resolution of symptoms.Acute/Late acute GVHD occurred in 4 patients. Three cases were noted in patients treated on the CD34-selected protocol; two MMUD (Grade III and Grade I) and one haploidentical (Grade III) graft recipients. One case of late acute liver GVHD, evident in elevation of liver enzymes and alkaline phosphatase with evidence of hepatitis on biopsy, occurred in a SIB recipient (Grade I). All cases responded to corticosteroid therapy.Conclusion:SCD patients with or without a SIB donor can be offered a curative HSCT that is safe without TRM. SCD patients with severe SCD-related organ damage can also be offered HSCT however further research is warranted to identify optimal conditioning and GVHD prophylaxis regimens for these patients. DisclosuresReshef:Kite Pharma: Consultancy; Atara Biotherapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda Pharmaceuticals: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

Higher Incidence of Graft Rejection in Non-Sibling Fully Matched Related Donor Stem Cell Transplants for Thalassemia Major: A Cautionary Note

▪Only 25-30% of patients with Thalassemia major (TM) will have a suitable HLA-matched sibling donor for an allogeneic SCT. In the absence of a HLA-matched sibling, an extended donor search within the family may yield a suitable donor, especially in societies with a high prevalence of consanguinity. We have previously reported inferior outcomes in patients who had a transplant from a non-sibling family donor. One of the criticisms of this was the issue of low resolution typing, which may have adversely impacted outcomes in some patients. We interrogated this data further to assess whether the poorer outcomes held up to scrutiny with the availability of high resolution HLA typing. Towards this we undertook a retrospective case-control study, adjusting controls for age and Lucarelli risk group (common confounders for clinical outcomes post-transplant in TM) with a 4:1 ratio of controls to cases.All consecutive patients with TM who had a stem cell transplant between the time periods 2007-2017, were included in this retrospective analysis. A total of 371 transplants were done with 281 matched sibling donor, 58 related donors (32 fully matched and 26 with 1-2 antigen mismatch), and 32 MUD donors (24 fully matched (10/10) and 8 with 1-antigen mismatch (9/10)).Subsequent to 2012, high resolution typing was done for all non-sibling related family donors. Of the 58 related donors, high resolution typing was available in 45, with twenty four 10/10 donors, nineteen 9/10 donors and two 8/10 donors. Further analysis was done in this sub-group (excluding the 8/10 donors), with rejection and death being considered as events. A control group from the fully matched sibling donor cohort was generated randomly after adjusting for age and Lucarelli Class.All patients received a myeloablative conditioning regimen (Busulphan/Treosulfan based). In-vivo T-cell depletion was done in 11 (45.8%) of matched related transplants and 54 (56.2%) of matched sibling donor transplants (P=0.359). A PBSC graft was used in 16 (66.7%) of matched related donor transplants compared with 36 (27.5%) of matched sibling donor transplants (P=0.012). There was no difference in the median CD34 cell dose achieved in both groups (Table 1). Table 1 shows baseline characteristics, transplant details and outcomes in the 10/10 matched related donors and fully matched sibling donor groups. Table 2 shows univariate and multivariate analysis for risk factors adversely affecting Thalassemia-free survival (TFS) using Cox regression analysis. The 2-year TFS in the 10/10 matched related donor group, 9/10 matched related donor group and fully matched sibling donor group was 56.8%±10.5%, 56.1%±11.9% and 81.8%±4% respectively (P=0.011) (Figure 1A). The 2-year overall survival (OS) in the 10/10 matched related donor group and 9/10 matched related donor group and the fully matched sibling donor group was 75.4%±9.9%, 64.5%±12.1% and 85.0%±3.7% respectively (P=0.168) (Figure 1B).This data on allogeneic transplants confirms our previous observations that there is a higher risk of graft rejection when the donor is a non-sibling related donor, even if fully matched on high-resolution typing (OR 4.8 ; 95% CI=1.3-18.2 : P=0.02). Transplant physicians must be aware this increased risk and counsel families appropriately. Further modifications in conditioning regimens and GVHD prophylaxis could potentially help in improving these outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of Non-Cryopreserved Peripheral Blood Stem Cells Is Associated with Adequate Engraftment in Patients with Multiple Myeloma Undergoing an Autologous Transplant

Autologous transplantation is the standard of care for transplant-eligible patients with multiple myeloma. Toward making this treatment accessible in developing countries, there are significant challenges like resource constraints and access to cryopreservation facilities. We performed a retrospective analysis of patients with multiple myeloma who underwent autologous transplantation using granulocyte colony-stimulating factor (G-CSF)-mobilized non-cryopreserved grafts at our institution from January 1995 to December 2014. Peripheral blood stem cells (PBSCs) were harvested over 1 to 2 days after G-CSF mobilization. After apheresis, PBSCs were stored at 4°C in a blood bank refrigerator for up to 72 hours. During the study period, 224 patients with multiple myeloma underwent autologous transplantation using G-CSF–mobilized non-cryopreserved grafts. The number of days of stem cell harvest was 1 in 91 patients (40.6%) and 2 in 133 patients (59.4%). The median CD34 cell dose was 4.87 × 106/kg (range, 1.15 to 23.7). All patients except 1 engrafted. The median time to neutrophil engraftment was 12 days (range, 9 to 22). The median time to platelet engraftment was 17 days (range, 10 to 44). In a resource-limited setting, the use of G-CSF–mobilized non-cryopreserved grafts results in adequate engraftment for most patients with multiple myeloma undergoing autologous stem cell transplantation.

Outcome of combination of HLA-haploidentical hematopoietic SCT with an unrelated cord blood unit for 127 patients with acquired severe aplastic anemia

目的评价单倍型造血干细胞移植（haplo-HSCT）联合第三方脐血干细胞移植治疗重型再生障碍性贫血（SAA）的疗效及安全性。方法对2011年9月至2017年4月间接受haplo-HSCT联合第三方脐血干细胞移植的127例SAA患者进行回顾性研究。结果全部127例SAA患者中，男74例，女53例，中位年龄23.5（3~54）岁，其中极重型再生障碍性贫血65例。诊断至移植中位时间2（0.5~180）个月。单倍型造血干细胞来源为骨髓+外周血。脐血均选用单份，HLA配型≥4/6相合。127例患者均接受改良Bu/Cy+ATG/ALG预处理方案（白消安+环磷酰胺+抗胸腺细胞球蛋白/抗淋巴细胞球蛋白）。以环孢素A、霉酚酸酯联合短程甲氨蝶呤预防GVHD。回输单倍型供者单个核细胞10.87（3.61~24.00）×108/kg，CD34+细胞3.49（1.02~8.89）×106/kg；回输脐血单个核细胞2.22（1.10~7.30）×107/kg，CD34+细胞0.56（0.16~2.27）×105/kg。127例患者中5例发生早期死亡。在可评估的122例患者中，1例发生原发植入失败，其余121例患者成功植入（均为单倍型造血干细胞植入）。中性粒细胞、血小板植入时间分别为11（9~28）d、15（9~330）d，5例患者发生血小板植入不良。移植过程中74例（58.27%）发生感染。存活患者中位随访20.5（4.0~60.0）个月，Ⅱ~Ⅳ度急性GVHD发生率为24.79%（30/121），中/重度慢性GVHD发生率为14.15%（15/106），预期4年总生存率为（78.5±4.3）%，无失败生存率为（77.4±4.3）%。结论haplo-HSCT联合第三方脐血干细胞移植治疗SAA疗效确切且安全性较好，在无全相合供者情况下可作为有价值的治疗选择。

Abstract 960: Defined cell composition and precise control over JCAR017 dose enables identification of relationships between chimeric antigen receptor T cell product attributes, pharmacokinetics, and clinical endpoints in NHL

Abstract JCAR017 is a CD19-directed 41BB chimeric antigen receptor (CAR) T cell product administered in a defined composition at a precise dose of CD8 and CD4 CAR T cells. JCAR017 manufacturing employs process controls that enable precise independent control of the infused dose of CD8 and CD4 cells. Preliminary safety data from JCAR017 administered in relapsed/refractory B cell non-Hodgkin lymphoma (NHL) demonstrated lower rates of cytokine release syndrome (CRS) and neurotoxicity (NT) compared to those reported for other CD19-directed CAR T cell therapies with heterogeneity in total infused dose and CD8 and CD4 composition. Multiple patient factors and blood biomarkers have been identified that correlate with JCAR017 CAR T cell in vivo expansion, antitumor activity, and toxicity (Heipel M et al. and Siddiqi T et al. ASH 2017). However, little is known regarding the contribution of CAR T cell product differentiation state to pharmacokinetics (PK), clinical outcome, or toxicity. Product characterization is executed on JCAR017 to define the CAR T cell memory phenotype composition and antigen-specific function. Product attributes were assessed for relationships with clinical response, safety, and PK through univariate, multivariate, and machine learning-based analyses. JCAR017 memory T cell composition demonstrated strong relationships with cytokine production profile observed following in vitro CD19 stimulation of the CAR T cell drug product. Specifically, products with elevated frequencies of CCR7+ central memory T cells exhibited increased production of IL-2 (Spearman ρ=0.55, P&amp;lt;0.0001), whereas patient drug product with increased frequencies of effector differentiated T cells demonstrated increased production of IFNγ (ρ=0.51, P&amp;lt;0.0001) and IL-13 (ρ=0.45, P&amp;lt;0.0001). The correlations between CAR T cell drug product memory phenotype and function translated to positive correlations between central memory subset composition and peak in vivo CAR T cell expansion (ρ=0.42, P=0.002) and progression-free survival (Kaplan-Meier survival estimate, P=0.0164). In addition, an increased frequency of a central memory subpopulation in drug product demonstrated relationships with CRS (P=0.0069) and severe NT (P=0.0014) events. The phenotype to functional links described above offer insights as to how specific memory subpopulations contribute to the complex CAR T cell mechanism of action. CAR T cell products with increased CCR7+ central memory composition demonstrated increased peak CAR T cell expansion and persistence, suggesting less differentiated CAR T cells contribute to PK and progression-free survival. These findings can be used to further define the next generation of gene-engineered T cell products (e.g., a fixed dose of CCR7+CAR+) that will decrease the dose-to-dose variability. Citation Format: Ryan P. Larson, Rachel Lower, Todd DeVries, Yue Jiang, Ronald J. Hause, Rich Getto, Brian Christin, Nathan K. Yee, Michael A. Bowen, Clinton Weber, Daniel Li, Tina Albertson, Claire Sutherland, Christopher G. Ramsborg. Defined cell composition and precise control over JCAR017 dose enables identification of relationships between chimeric antigen receptor T cell product attributes, pharmacokinetics, and clinical endpoints in NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 960.

Abstract 598: Utility of cell therapy to control relapsed acute myeloid leukemia following allogeneic stem cell transplantation: Does cell source matter

Abstract Introduction: Although allogenic hematopoietic stem cell transplantation (Allo-SCT) is curative therapy for acute myeloid leukemia (AML), many patients experience relapse following allo-SCT. For these patients, it is well known that donor lymphocyte infusion (DLI) could rescue a certain proportion via graft versus leukemia effect. On the other hand, with the advance of abundant stem cell harvesting techniques, residual stem cell after allo-SCT is also frequently used as a rescue therapy for AML relapse. However, clinical utility of residual stem cell is not well established yet. Hence, in this study, we compare the outcome of DLI with residual stem cell infusion in relapsed AML after allo-SCT. Materials and Methods: We retrospectively reviewed the AML patients who underwent DLI or residual stem cell infusion for relapsed disease after allo-SCT from 2001 to 2017 in Seoul National University Hospital. We analyzed factors including overall survival (OS), cell counts, disease status at cell therapy, and GVHD development. Our primary outcome was to compare OS after cell therapy between DLI group and residual stem cell group. Results: A total of 81 patients were analyzed. There were 50 patients (25 males and 25 females) who received cell therapy using DLI, and 31 patients (11 males and 20 females) who received residual stem cell infusion. There was no difference in age and duration from allo-SCT to cell therapy between the two groups. Majority of patients received cell therapy for first relapse after allo-SCT (63% in DLI, 93% in residual stem cell group). Median CD3 cell count infused was not different between DLI and residual stem cell product (median value of 0.967 X 108/kg and 0.964 X 108/kg). Median CD34 cell dose was 2.34 X 106/kg in residual stem cell group. There was no difference in OS between the two groups (median OS 8.5 months for DLI and 10.2 months for residual stem cell group, p-value 0.673). GVHD occurred in 44% in DLI group and 41.9% in residual stem cell group. When multivariate analysis was performed, disease status at stem cell therapy or duration from allo-SCT to relapse did not show any significant difference. Characteristics of long-term survivors after cell therapy following relapse after allo-SCT could be summarized as whether to acquire bone marrow CR after therapy. Conclusion: This study demonstrates that clinical utility of DLI and residual stem cell infusion is similar in relapsed AML after allo-SCT. Hence, residual stem cell could be used as an alternative source for T-cell therapy following allo-SCT. Citation Format: Woochan Park, Inho Kim, Sung-soo Yoon, Seonyang Park, Youngil Koh. Utility of cell therapy to control relapsed acute myeloid leukemia following allogeneic stem cell transplantation: Does cell source matter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 598.

600 - Increased CD34 Cell Dose is Associated with Rapid Immune Reconstitution after HSCT in Patients with Fanconi Anemia

600 - Increased CD34 Cell Dose is Associated with Rapid Immune Reconstitution after HSCT in Patients with Fanconi Anemia

Low CD34+ Cell Doses Are Associated with Increased Cost and Worse Outcome after Tandem Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Germ Cell Tumors

Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34+ cell doses > 5.0 × 106/kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 × 106 CD34+ cells/kg is challenging. We analyzed the effect of CD34+ cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34+ dose per transplant was 3.1 × 106/kg (range, 0.8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, 0.8 to 1.9 × 106/kg; Q2, 2.0 to 2.9 × 106/kg; Q3, 3.0 to 4.1 × 106/kg; and Q4, 4.2 to 16.0 × 106/kg. For all patients higher CD34+ cell doses were associated with significantly shorter times to neutrophil (P < .001) and platelet recovery (P < .001). For inpatient transplants higher CD34+ doses were significantly associated with shorter length of hospital stay (P < .001), fewer days of filgrastim (P < .001), i.v. antibiotic (P = .012) and antifungal (P = .03) usage; and fewer RBC (P = .001) and platelet units transfused (P < .001), resulting in overall lower cost of care (P < .001). Of the 142 planned outpatient transplants, 100 admissions were required for a median length of hospital stay of 7.0 days (range, 1 to 18). Although there was no significant difference in the rates of hospitalization between patients in different CD34+ cell dose quartiles, a significant trend was observed for shorter hospitalization (P = .01) and fewer RBC (P = .002) and platelet (P = .005) transfusions with higher CD34+ cell dose quartile. Patients receiving CD34+ cell doses in the lowest dose quartile (Q1) had significantly worse progression-free survival and overall survival compared with patients receiving higher CD34+ cell doses. Overall, resource utilization, including cost of care, is significantly reduced when patients receive higher CD34+ cell doses, indicating greater efforts to improve peripheral blood stem cell collection in this population are needed.

Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplantation in POEMS Syndrome: A Nationwide Survey in Japan

POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, λ-type M protein, vascular endothelial growth factor elevation, and systemic manifestations. The standard treatment has not been established, but autologous stem cell transplantation (ASCT) has exhibited effectiveness in this syndrome. However, the efficacy and long-term outcomes of ASCT have not been systematically studied. To clarify the efficacy and long-term outcomes of ASCT-treated patients in Japan, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation Transplant Registry Unified Management Program (TRUMP) database. Between January 2000 and December 2011, 95 patients (58 men) were registered to the TRUMP database with a median age of 53 years (range, 28 to 72). The conditioning regimen was melphalan in 93 of 94 patients (99%), and 69 patients (74.2%) received a melphalan dose ≥ 200 mg/m2. The median CD34 cell dose was 2.47 × 106/kg (range, .31 to 20). After ASCT, patient performance status was dramatically improved (Eastern Cooperative Oncology Group performance status 0 to 1: 20.0% versus 71.6%, P < .0001). Over a median follow-up of 46.6 months 10 patients died, and 5-year overall survival was 88.8% (n = 95). Progression-free survival at 3 years was 78.3% (n = 70; median follow-up, 54.4 months). These data support the promising role of ASCT in patients with POEMS syndrome for both prolonging survival and improving quality of life. However, disease recurrence remains a major issue for long-term survivors.

Phase 2 Trials with Mgta-456, Single Cord Blood Units (CBU) Expanded with an Aryl Hydrocarbon Receptor (AHR) Antagonist, Demonstrate Uniform Engraftment and Rapid Hematopoietic Recovery in Patients Following Myeloablative or Non-Myeloablative Conditioning

Background. The use of umbilical cord blood (UCB) in transplant has been limited by the low number of CD34+ cells, resulting in prolonged periods of cytopenia for patients and high risk of graft failure, thereby restricting its widespread application. MGTA-456 is the hematopoietic cell product after cord blood CD34+ cells are placed in expansion culture for 15 days with an aryl hydrocarbon receptor (AHR) antagonist in the presence of SCF, Flt-3L, IL-6 and TPO. In a prior Phase 1/2 safety study, 18 patients received MGTA-456, its accompanying CD34negfraction and a larger, unexpanded UCB unit. All patients engrafted at a median of 14.5 days (range, 7-23), significantly faster than similarly treated historical controls (p<0.01). Based on these results, two Phase 2 studies were initiated to evaluate the effectiveness of MGTA-456 as a stand-alone graft after myeloablative conditioning (MAC) or non-myeloablative conditioning (NMAC).Patients and Methods : Twenty patients with high-risk hematologic malignancy and a partially HLA-matched CBU were enrolled; 10 were treated with cyclophosphamide (CY) 120 mg/kg, fludarabine (FLU) 75 mg/m2 and total body irradiation (TBI) 1320 cGy (MAC) and 10 with CY 50 mg/kg, FLU 200 mg/m2 and TBI 200 cGy (NMAC). All patients received cyclosporine and mycophenolate mofetil post-transplant immunoprophylaxis. Expansion was low in 2 UCB units, therefore 18 patients received MGTA-456 and its CD34neg fraction.Results : Expansion culture yielded a median of 1,227 x 106 CD34+ cells (range, 201-8969) as compared to the input number of 4.2 x 106 (range, 1.4-16.3) after CD34 selection - a 324-fold (range, 42-1643) expansion of CD34+ cells. As transplant results vary by intensity of the conditioning, patient outcomes were compared to similarly treated historical cohorts between 2006 and 2015 (n=151 MAC; n=132 NMAC). For both groups, demographics were similar except for more recent year of transplant for recipients of MGTA-456. For recipients of MAC, MGTA-456 engrafted in all patients at a median of 14 days (range, 7-32) as compared to 89% engraftment at a median of 23 days (range, 19-31) in the control population (p<0.01, see Figure 1). Complete chimerism was rapid for both myeloid and T cells with no late graft failures; the longest follow-up was 5.6 years in recipients of MGTA-456. For recipients of NMAC, MGTA-456 also engrafted in all patients at a median of 7 days (range, 6-14) as compared to 94% engraftment at a median of 15 days (range, 7-22). In contrast to complete chimerism seen after MAC, chimerism is often mixed for the first month in both myeloid and T cells after NMAC. Compared to the historical cohort, recipients of MGTA-456 had more rapid chimerism after NMAC. CD34 cell dose correlates with speed of recovery but only in recipients with MAC; in recipients of NMAC, recovery is uniformly rapid regardless of CD34 cell dose. Additionally, immune recovery as measured by an absolute CD4 count >200/uL was achieved at day 60 (median) in recipients of MGTA-456 regardless of conditioning regimen. Results were also encouraging for other transplant outcomes. For recipients of MGTA-456 compared to the historical cohort after MAC, incidence of acute GVHD (aGVHD) grade 3-4 was 22% vs 24%; chronic GVHD (cGVHD), 11% vs 21%; transplant-related mortality (TRM), 11% vs 34%; and overall survival (OS), 67% vs 55%. After NMAC, results were similar between cohorts except for a higher risk of aGVHD in recipients of MGTA-456 (aGVHD 3-4, 43% vs 15%; cGVHD, 0% vs 19%; TRM, 22% vs 20%; and OS, 44% vs 49%). The increased rate of aGVHD in the NMAC cohort likely reflects non-compliance with prescribed GVHD immunoprophylaxis in 2 of 9 recipients.Conclusion : In these studies, MGTA-456 significantly accelerated hematopoietic recovery and abrogated the engraftment barrier typically associated with UCB transplantation. The marked expansion of CD34+ cells in MGTA-456 suggests that a significant number of patients will have an adequate single CBU and better HLA matched graft since a greater proportion of the cord blood inventory will be available irrespective of weight. Given these promising results, additional studies are being planned. [Display omitted] DisclosuresWagner:Novartis: Research Funding; Magenta Therapeutics: Research Funding. Brunstein:Novartis: Research Funding; Magenta Therapeutics: Research Funding. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties; Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. McKenna:Magenta Therapeutics: Research Funding; Novartis: Research Funding. Sanna:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Bleul:Hoffmann-La Roche AG: Employment. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties.

Reducing Gastrointestinal Toxicity Associated with Autologous Transplantation for Multiple Myeloma without Compromising Its Anti-Myeloma Effect

Early autologous hematopoietic stem cell transplantation (auto-HCT) is recommended for transplant-eligible patients (pts) with newly diagnosed multiple myeloma (MM). However, gastrointestinal toxicities, i.e., oral mucositis (OM), nausea and diarrhea, are the major limitation to the use of auto-HCT especially in the elderly population which constitute a significant proportion of MM pts, where the median age at diagnosis is 68 years. There is an unmet need for measures to minimize non-hematological toxicities without compromising melphalan anti-myeloma efficacy; this could lead to expansion of transplant eligibility to older pts. Amifostine, a FDA-approved cytoprotective agent to prevent OM for Head and Neck cancer, may reduce HDM-associated GI toxicity. We conducted a case-control study comparing auto-HCT with or without amifostine for MM pts.Methodspre-transplant amifostine has been incorporated to standard protocol for all MM patients underwent auto-HCT at University Hospitals Cleveland Medical Center (UH) for the last decade. One hundred and seven pts treated at UH who received amifostine, from January 2007 to July 2014, were compared to 114 matched-control pts treated at MD Anderson Cancer Center (MDACC) without use of this agent. The institutional review boards at both institutions approved the study. Amifostine 740 mg/m2 was administered as a bolus infusion at 24 hours and 15 minutes before HDM. All pts received ice chips peri-melphalan infusion. Survival outcomes were measured from the date of auto-HCT to the date of disease relapse or progression, Survival distribution was estimated using Kaplan-Meier methods. The effect of treatment on OS and PFS was estimated using a Cox model after controlling for the effects of age, gender, and number of prior therapies, time from diagnosis to transplant, Eastern Cooperative Oncology Group (ECOG) performance status and number of infused CD34+ cells.ResultsPts' characteristics were similar in both groups.Median follow-up of surviving pts was 35 (range 2-100) months in both cohorts. Amifostine therapy was well tolerated without any serious adverse effects. There was no significant difference between all-grade OM, nausea or vomiting between the two cohorts. However, > grade II GI toxicities were significantly lower in the amifostine group as follows: OM: 27.1% vs 47.4% (P=0.002), diarrhea: 56.1% vs. 72.7% (P=0.006), nausea: 31.8% vs. 86.0% (P=0.0001) and vomiting: 18.7% vs. 52.6%, (P=0.0001) (Figure-1) (Table-1). Median time to platelet engraftment was similar between the two groups while neutrophil engraftment period was shorter with use of amifostine (10 vs. 11 days, P=0.011) (Table-2). Multivariable logistic regression showed that use of amifostine pre-transplant was associated with a significant decrease in OM, diarrhea, nausea and vomiting. Pts who received amifostine and melphalan developed grade ≥ II OM significantly less often than those given melphalan alone with odds ratio (OR) = 0.366 (95% CI: 0.196-0.685, P=0.001; Table 3). Female gender was associated with a significant increase in OM, nausea and vomiting. Female pts were more likely to develop grade ≥ II OM with OR of 1.967 (P=0.017). Similarly, an ECOG performance status (PS) of ≥ 2 was associated with a significant increase in OM and diarrhea. For every additional score of ECOG, the risk of having grade ≥ II OM increased 1.89 fold (p=0.015). Subgroup analysis of grade II and higher OM rates are shown in Table-4. Use of amifostine was associated with reduced grade II or higher GI toxicity after adjusting for the effects of age, gender, number of prior therapies, time from diagnosis to transplant, ECOG PS and infused CD34 cell dose. There was no detrimental effect of amifostine on progression-free or overall survival.ConclusionsOur analysis indicates that the use of two amifostine doses of 740 mg/m2 before auto-HCT is safe and associated with significant reduction in grade II and higher GI toxicities without any deleterious effect on engraftment or anti-myeloma efficacy. Amifostine use could conceivably allow further melphalan dose-intensification for pts with resistant or high-risk disease. Also, pre-treatment with amifostine potentially could expand the utilization of auto-HCT for modestly frail MM pts that might not be considered eligible for this treatment modality. The protective effect of amifostine should be confirmed in randomized trial. [Display omitted] DisclosuresMalek:Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. Cooper:Novartis: Research Funding. Caimi:Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau; Seattle Genetics: Equity Ownership. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding.

Factors associated with peripheral blood stem cell yield in healthy pediatric donors

Background and ObjectivesAlthough several studies have reported on the use of children as donors for peripheral blood stem cells (PBSC), data on the predictive factors of CD34+ stem cell yield in healthy pediatric donors are very limited. Design and MethodWe retrospectively analyzed factors predicting the yield for a target CD34 cell dose of >3×106/kg recipient body weight in 140 apheresis in 100 healthy pediatric donors. The donors were evaluated in four groups assigned according to their ages of being 0–4 years, 5–9 years, 10–14 years and 15–18 years. 38 donors underwent second apheresis, two of which required third apheresis. ResultsMedian age and body weight were 9.8 years (range: 2–18 years) and 35.8kg (range 11–84kg), respectively. The median number of CD34+ cells in first apheresis was 3.9×106/kg of recipient body weight (RBW) (range: 0.03–33×106/kg RBW). Sixty–two out of 100 donors (62%) needed only one apheresis. The CD34+ cell count in stem cell product and the amount of CD34+ cell yield considering donors’ body weight obtained from the first apheresis was not statistically different among defined age groups. On multivariate analysis, variables that had a significant impact on CD34+ cell collection being more than 3×106kg RBW were donor to recipient weight ratio and periperal CD34+ cell count. ConclusionOur data suggest that CD34+ stem cell yield can be predicted from circulating CD34+ cell concentration on apheresis day and donor to recipient weight ratio in healthy pediatric donors.

Evaluation of Performance Status and Hematopoietic Cell Transplantation Specific Comorbidity Index on Unplanned Admission Rates in Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation

Although outpatient autologous stem cell transplantation (ASCT) is safe and feasible in most instances, some patients undergoing planned outpatient transplantation for multiple myeloma (MM) will need inpatient admission for transplantation-related complications. We aim to evaluate the difference, if any, between outpatient and inpatient ASCT cohorts of MM patients in terms of admission rate, transplantation outcome, and overall survival. We also plan to assess whether the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and Karnofsky Performance Status (KPS) can predict unplanned admissions after adjusting for confounding factors. Patients with MM (n = 448) who underwent transplantation at our institution between 2009 and 2014 were included in this retrospective analysis. Patients were grouped into 3 cohorts: cohort A, planned inpatient ASCT (n = 216); cohort B, unplanned inpatient admissions (n = 57); and cohort C, planned outpatient SCT (n = 175). The statistical approach included descriptive, bivariate, and survival analyses. There were no differences among the 3 cohorts in terms of type of myeloma, stage at diagnosis, time from diagnosis to transplantation, CD34 cell dose, engraftment kinetics, and 100-day response rates. Serum creatinine was higher and patients were relatively older in both the planned inpatient (median age, 62 years; range, 33 to 80 years) and unplanned (median age, 59 years; range, 44 to 69 years) admission cohorts compared with the outpatient-only cohort (median age, 57 years; range, 40 to 70 years) (P < .05). Performance status (cohort A: median, 90%; range, 60% to 100%; cohort B: 80%, 50% to 100%; cohort C: 80%, 60% to 100%) was lower (P < .05) and HCT-CI score (cohort A: median, 1.78; range, 0 to 8; cohort B: 2.67, 0 to 9; cohort C: 2.16, 0 to 7) was higher (P < .004) in both inpatient groups compared with the planned outpatient cohort. With a median follow up of 5 years, poor performance status (KPS <70%) appeared to be associated with worse survival (P < .002). HCT-CI >2 also appeared to be associated with worse outcomes compared with HCT-CI 0 to 1, the the difference did not reach statistical significance (hazard ratio, 1.41l 95% confidence interval, 0.72 to 2.76). Only 1 patient out of 448 died from a transplantation-related cause. Outpatient transplantation for myeloma is safe and feasible. In our experience, one-third of the patients undergoing outpatient transplantation needed to be admitted for transplantation-related toxicities. Patients in this group had lower preexisting KPS and higher HCT-CI scores. Whether planned admission for this group would have prevented unplanned admissions and undue stress on patients and the healthcare system should be tested in a prospective manner.

Improved planning of leukapheresis endpoint with customized prediction algorithm: minimizing collection days, volume of blood processed, procedure time, and citrate toxicity.

Increased emphasis on cost and productivity in apheresis centers calls for a proficient and predictable hematopoietic progenitor cell (HPC) collection. Therefore, the aim of this study was to determine the value of a customized predictive algorithm that estimates how many blood volumes are required to process for a targeted CD34 cell dose. Retrospective analysis was performed on 107 HPC collections completed on the Spectra Optia MNC from January 2013 to June 2014 in 51 patients and 12 donors. In December 2014, a prediction algorithm was implemented, designed from data acquired since January 2013, by linear regression of preapheresis CD34 cell counts (pre-CD34) versus collected CD34 cell dose per volume blood processed. CD34 collection efficiencies (CE2) of 51.9±1.7% (mean±SEM) and 57.5±3.0% were observed in autologous and allogeneic procedures, respectively. After implementation of the algorithm, the mean number of collections per patient declined from 1.97 to 1.5. Accordingly, the frequency of patients requiring single-day collections increased from 35% to 57%. All donors were collected in single procedures, although only 12.2±1.1L blood was processed, including for National Marrow Donor Program collections. Cumulative procedure time, processed blood volume, product volume, infused anticoagulant volume, and symptomatic calcium administration decreased in patients, and overcollection was limited. A prediction algorithm can provide great value in the planning of leukapheresis, which may optimize resource utilization and capacity of the unit. In addition, predictability was facilitated by a proficient and consistent performance of the Spectra Optia MNC.

High Peripheral Blood Stem Cell (PBSC) CD34+ Cell Dose Increases the Risk of Chronic Gvhd after Human Leukocyte Antigen (HLA) Matched Sibling Transplantation

CD34+ cell dose is a critical determinant of outcomes after allogeneic PBSC transplantation, with a CD34 dose ≥2.0 x 10e6/kg shown to positively impact hematopoietic engraftment and survival. However, it is unknown whether additional benefits are observed with even higher CD34 cell doses. Therefore, we further explored the effect of intermediate, high and very high CD34 cell doses on the incidence of engraftment, acute and chronic graft-versus-host disease (GVHD) and transplant related mortality (TRM) and on probability of survival and GVHD-Relapse-free survival (GRFS). Three hundred and five consecutive patients transplanted with GCSF-mobilized PBSC from HLA-matched sibling donors (MSD) were evaluated. Patients were ≥16 years of age, had a hematological malignancy and received a myeloablative or a nonmyeloablative conditioning regimen between 2002 and 2012. The median recipient age was 52 years (r, 19-74 years) with most being male (n=194, 63.8%) diagnosed with leukemia (72%) or lymphoma (22%), and intermediate disease risk index (DRI, n=204, 67%). The median age for the donor were 49 years (r,17-76 years). In 159 patients (52%) the donor and recipient were sex matched with 89 male patients having a female door (29%). The ABO blood type was matched in 195 patients (64%), 153(50%) received a myeloablative (MA) conditioning regimen, and 37 (12%) received a reduce intensity conditioning regimen containing ATG. The median follow up of surviving patients was 793 days (r, 14-4562 days). Patients were divided in four CD34 dose quartiles: first quartile (QT1), ≤4.8 x10e6/kg, QT2 4.8-6.0 x10e6/kg, QT3 6.0-7.5 x10e6/kg, and QT4 ≥ 7.6 x 10e6/kg. Notably, the CD3 doses were similar for all quartiles: QT1 was 3.4 x 10e8/kg (r, 0.3-10.0), QT2 was 2.7 x 10e8/kg (r, 1.1-7.6), QT3 was 2.8 x 10e8/kg (r, 0.8-7.2) and QT4 was 2.8 x 10e8/kg (r, 1.4-7.7); there was no correlation between CD34 and CD3 cell doses. Patient and donor characteristics were similar in the four groups except for shorter median follow-up (P <0.01) in QT1, more sex mismatched grafts (P <0.01) in QT3, and lower median number of cell collections (P <0.01) and more female donor: male recipient pairs (P< 0.01) in QT4. Multivariate analysis results are summarized on the table. Higher CD34+ cell dose was associated with improved platelet recovery with trends toward lower TRM and improved overall survival. Chronic GVHD however was also higher. In summary, additional studies are needed to establish a survival benefit in recipients of higher cell doses >4.8 x 10e6 CD34 cells/kg. Unless survival is positively impacted, the higher risk of chronic GVHD would argue for assigning an upper CD34 cell dose limit to reduce this risk that can significantly impair quality of life. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Doses of Total Nucleated Cells and Activated T-Cells Transplanted Influence Survival and Graft Versus Host Disease Among AML and MDS Recipients of Reduced-Intensity Mobilized Peripheral Blood Allografts

Background: Patients undergoing allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning (RIC-alloSCT) rely primarily on the graft-versus-tumor (GVT) effect to prevent relapse. Although relapse remains high in this setting, previous data suggest modifications of allograft composition could produce enhanced GVT effect and improve outcomes. Prior retrospective studies suggested higher total nucleated cell (TNC) and CD8 dose correlate with improved overall survival (OS) and a reduction in relapse among all patients undergoing RIC-alloSCT. The aim of our study was to further investigate this association by comparing transplant outcomes with detailed graft immunophenotyping data including T-cell and NK-cell activation and maturation status and CD34 cell doses in patients with AML and MDS undergoing RIC-alloSCT.Methods: We performed a retrospective analysis using data from consecutive patients with AML and MDS who underwent RIC-alloSCT at a single center from 2010-2015 who had graft immunophenotyping data available. We compared transplant outcomes with TNC per kilogram (kg) and dose of CD3, CD4, CD8, CD34, and NK cells along with selected activation and maturation subsets. A competing risk regression analysis was conducted to examine the association between cell dose/kg and risk of relapse and graft versus host disease (GVHD). Overall survival and relapse free survival (RFS) were assessed utilizing the Cox proportional hazard model. Estimates of survival probability were determined by the Kaplan-Meier survival function. The log-rank test was used to compare OS and RFS among patients. Univariable and multivariable regression analyses were performed. Disease Risk Index (DRI) was used to stratify risk among patients. To identify optimal cutoffs (OC) of continuous variables for a specific outcome, a Classification and Regression Tree (CART) algorithm was utilized.Results: Our study included 142 patients who underwent RIC-alloHSCT for AML (n=97, 68%) and MDS (n=45, 32%). The vast majority of patients (98%) received fludarabine and busulfan conditioning with 65% receiving anti-thymocyte globulin. All patients received tacrolimus-based GVHD prophylaxis. Overall relapse rate was 37% at 3 years. Overall survival was 49% with median follow-up of 3.2 years.Total Nucleated Cell Dose: In multivariable analysis controlling for disease, comorbidity index, and performance status, a high infused TNC dose (10.6 - 16.8 x 108 cells/kg) correlated with improved overall survival (HR 0.27, 95% CI [0.12 - 0.59], p=0.001) and relapse free survival (HR 0.31, 95% CI [0.15 - 0.64], p=0.002). However, a very high TNC dose (OC >16.8 x 108 cells/kg) correlated with significantly worse OS (HR 2.84, 95% CI [1.16 - 6.98], p=0.023) and trended toward worse RFS (HR 2.09, 95% CI [0.88 - 4.93], p=0.093). Higher TNC doses were also correlated with an increased risk of chronic GVHD (HR 2.16, 95% CI [1.28 - 3.67], p=0.004, OC 9.8 x 108 cells/kg).Cell Subsets: Very low CD3 cell doses (OC <1.06 x 108 cells/kg) correlated with worse OS (HR 3.30, 95% CI [1.23 - 8.85], p=0.017) and worse RFS (HR 2.64, 95% CI [1.01 - 6.88], p=0.047). High CD3 doses were correlated with an increase in acute GVHD (all grades) (HR 2.41, 95% CI [1.36 - 4.25], p=0.002, OC 4.1 x 108 cells/kg). NK, CD4, CD8, and CD34 cell dose was not associated with relapse, OS, or RFS in multivariable analysis. Utilizing a previously published (Reshef et al, JCO, 2015) cutoff of 7.2 x 108 cells/kg, there was a trend toward a reduction in relapse with higher CD8 cell dose, but this did not reach statistical significance (HR 0.67, 95% CI [0.39 - 1.16], p=0.15). A high dose of late activated T-cells (CD3+/HLA-DR+) correlated with increased risk of acute GVHD (HR 2.31, 95% CI [1.26 - 4.20], p=0.006, OC 2.01 x 107 cells/kg) and chronic GVHD (HR 1.85, 95% CI [1.12 - 3.07], p=0.016, OC 6.6 x 106 cells/kg).Conclusion: Among AML and MDS patients following RIC-alloSCT, higher infused TNC/kg was associated with improved RFS and overall survival, confirming findings from a recent study (Martin et al, Haematologica, 2016). However, very high TNC doses may be deleterious. T-cell activation state influences risk of GVHD. Further research needs to be pursued to corroborate these findings and potentially optimize TNC and T-cell doses. We were unable to identify a significant correlation between CD8 cell dose and relapse or overall survival. [Display omitted] [Display omitted] DisclosuresLozanski:Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.