Older Adults with Chronic Myelogenous Leukemia (CML), During the Tyrosine Kinase Inhibitor (TKI) Era, Can Be Successfully Treated with Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplant (HCT) Using Sibling or Unrelated Donors: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Abstract Abstract 494 The introduction of tyrosine kinase inhibitors (TKI) and advent of RIC and non-myeloablative (NMA) conditioning hematopoietic cell transplants (HCT) have changed and the therapeutic strategy for patients with CML. We analyzed the post HCT outcomes of CML patients aged 40 and older undergoing RIC/NMA HCT in 2001–2007. Detailed information regarding pre HCT TKI use or rationale for timing of transplant was not available; however, the analysis time period captures the entry of TKIs into clinical practice. Outcomes were compared between age cohorts of 40–49, 50–59, and ≥ 60 years. Overall survival (OS), Day +100 acute graft versus host disease (aGVHD) grades II-IV, chronic (cGVHD), transplant-related mortality (TRM), relapse, and disease-free survival (DFS) were analyzed with multivariate analysis testing the impact of age, gender, disease status at HCT (CP1vs. CP2/accelerated phase (AP) vs. blast phase (BP), sex match, HLA match, GVHD prophylaxis, and conditioning intensity (RIC versus NMA as described by Bacigalupo et all 2009) on outcomes. A total of 306 CML patients underwent HCT at 125 centers: 117 (38%) aged 40–49; 119 (39%) aged 50–59; and 70 (23%) aged ≥ 60. At HCT most patients in the 40–49 age cohort were in CP1 (72%), while only 44% of patients aged 50–59 and 31% aged ≤ 60 were in CP1. Interval from diagnosis to HCT for CP1 patients was similar across age groups with a large percentage of each age cohort undergoing HCT ≥ 2 years (32%, 40%, and 45%, respectively). Sibling donors were the stem cell source for 56% of those aged 40–49; older cohorts had a higher percentage of unrelated donors (58 and 60%, respectively). Primarily peripheral blood grafts (78%, 80% and 90%) and RIC (78%, 76% and 70%) were used across age groups, respectively. GVHD prophylaxis was similar. Three year OS and cGVHD, Day +100 grade II-IV acute GVHD, and 1 year TRM were similar in all age cohorts. Three year relapse incidence increased and DFS decreased with age. Importantly in analysis of CP1 patients only, relapse and DFS were similar in each age cohort.Table 1:Univariate AnalysisOutcomeAge 40–49 Probability (95% CI)Age 50–59 Probability (95% CI)Age ≥ 60 Probability (95% CI)P-valueEntire CohortOSA54% (44–64)52% (42–61)41% (30–54)0.26aGVHDB II-IV26% (18–34)32% (24–40)32% (21–43)0.53cGVHDA58% (47–68)51% (41–61)43% (33–55)0.19TRMC18% (11–26)20% (13–27)13% (6–22)0.43RelapseA36% (27–46)43% (34–52)66% (53–77)0.001DFSA35% (26–45)32% (24–41)16% (7–27)0.01CP1 OnlyRelapseA34% (23–46)42% (28–56)51% (29–72)0.40DFSA43% (31–55)36% (23–51)39% (19–61)0.81A=3 year; B=Day +100; C=1 year Multivariate analysis confirmed the significant adverse impact of advanced CML (AP/CP2+ and BP) at HCT, NMA conditioning intensity, male gender, and older age on relapse and DFS. Overall survival was not impacted by age, but was significantly worse with advanced CML at HCT. (Table 2)Table 2:Multivariate AnalysisOutcomeRR95% CIP valueRelapse:Age:10.69–1.6420.000340–491.0641.441–3.60750–592.28≥60Disease Status:10.1319–0.9170.01CP11.3350.0036–1.403AP/CP2+2.823BPConditioning Intensity10.222–0.469<0.0001NMA0.323RICGender10.397–0.830.0032Male0.574FemaleOverall SurvivalAge:10.55–1.2260.4240–490.8210.683–1.61850–591.051≥60Disease Status:11.206–2.47<0.0001CP11.7263.199–10.0740.42AP/CP2+5.677BPGender:10.0189–0.4810.019Male0.671Female These data indicate that HCT is safe in older patients with CML with equivalent acute and chronic GVHD, TRM, and OS across age cohorts. Relapse increased in patients receiving NMA conditioning and in those aged 60 and above; most of whom had advanced disease. However, for HCT during CP1 relapse risks and DFS were similar, regardless of age. Allogeneic HCT using RIC conditioning for older patients with CP1 CML can control relapse with acceptable toxicity and survival. Comparison of outcomes with second line TKI versus HCT are as yet unreported but these favorable findings indicate appropriate consideration of HCT for older patients with CML. Disclosures: Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Multicenter Microbiota Analysis Indicates That Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival

Blood ◽

10.1182/blood-2018-99-116967 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 811-811

Author(s):

Jonathan U. Peled ◽

Antonio LC Gomes ◽

Christoph K. Stein-Thoeringer ◽

John B. Slingerland ◽

Ann E. Slingerland ◽

...

Keyword(s):

Overall Survival ◽

Healthy Volunteers ◽

Board Of Directors ◽

Calorie Intake ◽

Advisory Committees ◽

Poor Overall Survival ◽

Gvhd Prophylaxis ◽

Α Diversity ◽

Low Diversity ◽

Conditioning Intensity

Abstract Intestinal microbiota composition is associated with important outcomes after allo-HCT including survival, relapse, GVHD, and infections. These observations have been made almost exclusively by characterizing the microbiota in the first weeks after transplantation, and in single-center studies. We previously reported that intestinal diversity measured peri-neutrophil engraftment is predictive of overall survival in a multicenter cohort. Here, we hypothesized that pre-HCT microbiota configuration may also be an important determinant of post-transplantation outcomes. We report a multicenter analysis conducted at 4 independent international institutions to test this hypothesis. We collected 1922 stool samples ~weekly from 991 unique allo-HCT patients at four international transplant centers: Cohorts 1 and 2 in the US, cohort 3 in Europe, and cohort 4 in Japan. The patients-all adult recipients of allo-HCT-varied in underlying diagnosis, donor-graft sources, conditioning intensity, and GVHD prophylaxis. Samples from all 4 centers were sequenced and analyzed at a central laboratory using the V4-V5 region of 16S rRNA. For patients with multiple samples within the pre-HCT sampling period, which we defined as day -20 to 0, median values were used. On average, patients from all 4 transplantation centers had reduced microbiota diversity pre-HCT, as measured by median α-diversity (inverse Simpson) values that were 1.7-to-2.5-fold lower than those of healthy volunteers. This comparison was made both in volunteers whose samples we sequenced ourselves and in a publicly available dataset (Fig A, p<0.005). Since α-diversity measurements do not consider which taxa are present in a community, we asked whether the composition of pre-HCT microbiotas are similar to healthy microbial communities. While the intestinal communities of most healthy volunteers could be matched to the Enterotypes classifier, pre-HCT samples from all four centers had configurations that were poorly characterized by this independent classification scheme (Fig B). Thus, the post-HCT microbiota injuries that we previously observed comparably across geography are preceded by community structures that are already abnormal pre-HCT, consistent with our prior observation that pre-HCT antibiotic exposure is a risk factor for poor outcomes. We next asked how similar these pre-HCT communities are across geography. We found that Bray-Curtis distances between institutions were reproducibly much smaller in magnitude than the changes observed over time during transplantation (Fig C, p<0.005). We also observed in the largest cohort (#1) that pre-HCT diversity is associated with patient survival. Among 753 patients, those in the lowest quartile of pre-HCT α-diversity had a lower overall survival than those in the highest quartile (Fig D, p<0.009). In order to characterize these clinically relevant low-diversity phenotypes, we defined domination as a microbiota injury in which any operational taxonomic unit comprises >30% of bacterial abundance. The dominating taxa belonged to multiple genera, the most common being Enterococcus, Streptococcus, Lactobacillus, Escherichia, and Klebsiella (Fig E) as annotated by Greengenes and NCBI databases. At all four institutions, the cumulative incidence of intestinal domination by any organism was >50% by day 0 and was >87% by day +28 (Fig F). We performed additional analyses in the largest cohort and found that the low-diversity state is associated with exposure to broad-spectrum antibiotics, conditioning intensity, and low calorie intake. We demonstrate that HCT patients at 4 institutions on 3 continents presented with microbiota configurations that were similar to one another and distinct from those of healthy individuals. Severe microbiota injury as revealed by domination is a common event whose development begins before allograft infusion, and pre-HCT microbiota injury predicts poor overall survival. These observations suggest the pre-HCT period as a window of opportunity to (a) assess microbiota injury as part of comorbidity evaluation, (b) inform selection of antibiotic prophylaxis, gut-decontamination, GVHD-prophylaxis, or conditioning regimens, and (c) intervene with microbiota injury-remediation or prevention strategies. Figure. Figure. Disclosures Peled: Seres Therapeutics: Research Funding. Perales:Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support. Jenq:MicrobiomeDx: Consultancy; Ziopharm Oncology: Consultancy; Seres Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics, Inc.: Patents & Royalties.

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Trends in All-Cause Mortality Among Older Patients with CML: A SEER Database Analysis

Blood ◽

10.1182/blood.v120.21.3772.3772 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3772-3772

Author(s):

Andrew M. Brunner ◽

Federico Campigotto ◽

Benjamin J. Drapkin ◽

Hossein Sadrzadeh ◽

Donna S. Neuberg ◽

...

Keyword(s):

Overall Survival ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Older Patients ◽

Kinase Inhibitors ◽

Age Groups ◽

Relative Survival ◽

Age Group ◽

Seer Database ◽

Advisory Committees

Abstract Abstract 3772 Introduction: Clinical outcomes for patients with chronic myeloid leukemia (CML) have dramatically improved over the course of the past ten years, following the advent of tyrosine kinase inhibitors (TKIs) that target BCR/ABL. Nonetheless, survival differences persist between age groups. Prior analyses suggested that this difference occurs in part due to treatment variation; in Sweden, patients older than age 79 had poorer relative survival, and more typically were treated with hydroxyurea rather than a TKI [Bjorkholm, J Clin Oncol 29:2514]. Other studies have noted gains made in relative survival up to the year 2004 [Brenner, Haematologica93:1544], but longer-term overall survival following the widespread use of TKI therapy is less well described among older patients in the U.S. We performed an epidemiologic study of patients registered in the Surveillance, Epidemiology, and End Results (SEER) database to estimate the 5 year overall survival (OS) of patients treated for CML in the era of TKI therapy to assess for differences in survival outcomes among patients within different age groups. Methods: Patients with a diagnosis of CML were identified using the SEER 19 registries database [www.seer.cancer.gov, 1973–2009, November 2011 submission]. We included patients with a diagnosis code of CML NOS (Code 9863) and BCR/ABL+ CML (Code 9875) diagnosed between January 2000 and December 2005. This interval brackets the FDA approval of imatinibin 2001, and its incorporation into NCCN guidelines in 2003. To reflect the evolution of CML treatment during this interval, we trended 5-year overall survival by the year of initial diagnosis. To evaluate the effect of age on survival, patients were divided into cohorts based on age at diagnosis: 15–44 years old, 45–64 years old, 65–74 years old, and 75–84 years old. Overall survival was estimated using the method of Kaplan and Meier. Cox proportional hazards regression was used to model OS to estimate the effects of year of diagnosis within each age group. All analyses were performed using SAS statistical software. Results: We identified 5,138 patients registered in the SEER database with a new diagnosis of CML between January 2000 and December 2005. The patients were 57.6% male; this was the first recorded primary malignancy for 88.4% of the cohort. The 5-year OS improved among patients in every age group between the years 2000 and 2005 (Table 1, Figure 1). Compared to patients diagnosed in the year 2000, patients between the ages of 15 and 44 years had the greatest improvement in 5 year OS (Figure 1; hazard ratio (HR) for dying 0.427, 95% CI: [0.278;0.655], P<0.0001). Patients between ages 75 and 84 also had significant survival gains; the OS estimate at 5 years increased from 19.2% in 2000 to 36.4% in 2005 (HR for dying 0.571, 95% CI: [0.443;0.736], P<0.0001). Discussion: Tyrosine kinase inhibitors targeting BCR/ABL have been FDA-approved for the treatment of CML since 2001 and are highly effective therapy for this disease. Since their advent, patient survival has improved among all age groups; intriguingly, this is also seen among older patients. Indeed, we found marked improvements in OS at 5 years among patients between the ages of 75 and 84, a group which historically has had very poor outcomes. Our data suggests that the advent of BCR/ABL tyrosine kinaseinhibitors has had a significant impact on the outcomes of older patients with CML, likely by providing them with tolerable and effective treatment options not previously available. Further study is needed to determine specific factors that contribute to this improvement in survival. In the future, older age groups are likely to experience ongoing benefit from novel and effective therapeutics with tolerable side effect profiles. Disclosures: Fathi: Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia (AML): Princess Margaret Cancer Centre Experience

Blood ◽

10.1182/blood-2019-125449 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2609-2609

Author(s):

Muhned Alhumaid ◽

Georgina S Daher-Reyes ◽

Wilson Lam ◽

Arjun Law ◽

Tracy Murphy ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Treatment Strategies ◽

Patient Characteristics ◽

Cancer Center ◽

Advisory Committees ◽

Disease Behavior

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: 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, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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The Abundance of Certain Bacteria in the Intestinal Flora Is Associated with Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.744.744 ◽

2015 ◽

Vol 126 (23) ◽

pp. 744-744 ◽

Cited By ~ 2

Author(s):

Jonathan Peled ◽

Eric R. Littman ◽

Lilan Ling ◽

Satyajit Kosuri ◽

Molly Maloy ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Intestinal Flora ◽

Advisory Board ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Streptococcus Anginosus ◽

Conditioning Intensity

Abstract The major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are relapse, graft-versus-host disease (GVHD), and infection. We have previously reported that changes in the intestinal flora can affect GVHD, bacteremia, and overall survival. As intestinal bacteria are potent modulators of systemic immune responses, and since GVHD is correlated with graft-versus-tumor activity, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HSCT. We applied a biomarker-discovery approach and performed a retrospective observational analysis of 160 adults who received an unmodified (T-cell-replete) allograft. Patients were prospectively enrolled in a fecal biospecimen-collection protocol. For this analysis, we selected patients who had at least one specimen during the first 3 weeks following allo-HSCT. The primary diseases in this cohort were AML (37%), Non-Hodgkin's Lymphoma (33%), ALL (8%), MDS (7%), CLL (6%), Hodgkin's Lymphoma (6%), CML (2%), and myeloproliferative neoplasm (2%). The mean age of the patients was 52 years (range 21-75). They were conditioned with ablative (17%), reduced-intensity (64%), and nonmyeloablative (19%) regimens. They received grafts from cord blood (46%), unrelated adults (33%), or related adults (22%). Among adult grafts, 92% were from peripheral blood and 8% were from bone marrow. A census of the bacterial species in each stool sample was generated by 16S rRNA deep-sequencing as previously described (Jenq et al., BiolBone Marrow Transplant 2015). The area under the curve of bacterial abundance over time was used as a measure of each patient's cumulative exposure to each bacterial taxon. Bacterial taxa of each patient present at a frequency >1% were evaluated for association with the outcome of relapse or progression of disease within the first year after allo-HSCT using linear discriminant analysis of effect size (LEfSe), a common approach in microbiota studies (Segata et al., Genome Biology, 2011). Among the taxons most significantly associated with freedom from relapse were members of the human oral flora including Streptococcus anginosus. After stratifying the patients by median abundance, we found that those with higher abundance of this bacterium had less relapse after transplantation (Left figure, p = 0.0014). We also identified bacteria associated with increased risk of relapse, such as Enterococcus faecium (Right figure, p = 0.0103). We evaluated these bacteria as biomarkers in multivariate Cox models adjusted for three factors that were associated with relapse in this cohort: Refined Disease Risk Index (RDRI, Armand et al., Blood 2014), conditioning intensity, and graft source (cord blood vs. adult donor). Streptococcus anginosus predicted relapse in a multivariate model adjusted for all three factors (HR 0.39, 95% CI 0.16-0.96, p = 0.041). Enterococcus faecium predicted relapse in a model adjusted for RDRI and conditioning intensity but failed to do so in a model additionally adjusted for graft source. In this analysis there was no formal adjustment for multiple comparisons; these data are now being validated in an additional cohort of patients whose samples are being sequenced. Finally, although we have previously reported that low bacterial diversity is associated with decreased overall survival after allo-HSCT (Taur et al., Blood 2014), we did not find an association between bacterial diversity and relapse as assessed by reciprocal Simpson diversity index (p > 0.1). Thus, the results of this retrospective analysis have identified an association between relapse after allo-HSCT and the abundance of two bacteria in the intestinal flora. These might serve as potential novel diagnostics or therapeutic targets to prevent relapse and improve overall survival after allo-HSCT. Figure 1. Figure 1. Disclosures Peled: Merck: Research Funding. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Research Funding. Perales:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Astellas: Honoraria; NMDP: Membership on an entity's Board of Directors or advisory committees. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee; Regeneron: Honoraria; Merck: Honoraria.

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Updated Outcomes of Fludarabine/Melphalan/Bortezomib (Flu/Mel/Vel) Conditioning for Upfront Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5885.5885 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5885-5885

Author(s):

Taiga Nishihori ◽

Claudio Anasetti ◽

Rachid Baz ◽

Jose L Ochoa-Bayona ◽

Kenneth H. Shain ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Advisory Committees ◽

Allogeneic Hct ◽

Genetics Research ◽

Gvhd Prophylaxis ◽

Unrelated Donors

Abstract Background: Multiple myeloma remains incurable despite impressive array of available novel agents and therapeutic strategies. Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative option for patients with multiple myeloma but it is limited by its toxicities. We previously reported initial result of a phase 2 study of upfront allogeneic HCT in myeloma patients achieving at least very good partial response (VGPR) after initial therapy (Nishihori, et al. ASH 2013 abstract 3390) and here we report more mature results after a median follow up of 3 years. Methods: Twenty seven myeloma patients received allogeneic HCT between 01/2010 and 02/2015 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60, achieving first ≥ VGPR or complete response (CR), and have 8/8 HLA-matched related or unrelated donors. Conditioning regimen consisted of fludarabine 30 mg/m2 for 4 days (days -6, -5, -4, and -3) and melphalan 70 mg/m2 for 2 days (days -4 and -3) followed by a single dose of bortezomib 1.3 mg/m2 on day -3 (Flu/Mel/Vel regimen). GVHD prophylaxis was initially left to the discretion of physicians but later modified to only tacrolimus/methotrexate. No maintenance therapy was prescribed after allogeneic HCT. Results: The median age at transplant was 50 (range, 25-58) years. Disease status at the time of allogeneic HCT was VGPR (n=17: 63%) and CR/stringent CR (n=10: 37%). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched related donors (n=14) or HLA-matched unrelated donors (n=13). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus either methotrexate (n=19: 70%), or mycophenolate mofetil (n=4), or sirolimus (n=4). All patients achieved neutrophil engraftment with a median of 15 (range, 11-19) days. Platelet engraftment was achieved with a median of 17 (range, 13 - 35) days and 2 patients did not recover platelets. The cumulative incidences of grades II-IV and grades III-IV acute GVHD at day 100 were 63.6% (95% confidence interval (CI): 43.1-81.1) and 19.6% (95%CI: 5.4-39.9), respectively. The cumulative incidence of moderate to severe chronic GVHD was 56.4% (95%CI: 36.3-75.5) at 1-year. The cumulative incidences of transplant-related mortality at day 100, 1 year and 2 years were 7.4% (95%CI: 0.8-20.0), 11.1% (95%CI: 2.7-25.4), and 11.1% (95%CI: 2.7-25.4), respectively. Progression-free survival estimates at 1, 2, and 3 years were 74.1% (95%CI: 53.2-86.7), 65.1% (95%CI: 43.3-80.2), and 65.1% (95%CI: 49.9-87.5), respectively. With a median follow up of 39 months for surviving patients, overall survival estimates at 1, 2 and 3 years were 85% (95%CI: 64.9-94.1), 75.4% (95%CI: 52.6-88.3), and 69.1% (95%CI: 53.8-93.5), respectively. Conclusions: The results of the this phase 2 trial of upfront allogeneic HCT with fludarabine/melphalan/bortezomib (Flu/Mel/Vel) conditioning are promising and provide the rationale for reasonable potentially curative option to younger and fit patients who are eligible for upfront intensive consolidation strategy. This approach may be potentially valuable for those with high-risk myeloma and a multicenter study is currently being conducted (BMT CTN protocol 1302:NCT02440464). Disclosures Nishihori: Novartis: Research Funding; Signal Genetics: Research Funding. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Bristol-Myers Squibb: Research Funding; Signal Genetics: Research Funding. Shain:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Alsina:Signal Genetics: Consultancy; Novartis: Research Funding; Takeda/Millennium: Research Funding; Amgen/Onyx: Consultancy, Speakers Bureau.

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Osteosarcoma: A Comparison of Jaw versus Nonjaw Localizations and Review of the Literature

Sarcoma ◽

10.1155/2013/316123 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

H. van den Berg ◽

W. H. Schreuder ◽

J. de Lange

Keyword(s):

Older Patients ◽

Age Groups ◽

Incidence Rates ◽

Steady Increase ◽

Review Of The Literature ◽

Tumor Patients ◽

Age Cohorts ◽

Age Cohort ◽

Steep Decline ◽

Age Range

Purpose. It is assumed that osteosarcomas of the jaws mainly occur at older ages, whereas the most prominent sites, that is, the long bones, are more affected at ages <20. Jaw-localized tumors are less malignant and have lower metastatic spread rates.Patients and Methods. This study analyses the nationwide data of the Dutch Cancer Registry on osteosarcoma during the period from 1991 to 2010. Age-corrected incidence rates were calculated.Results. In 949, 38 patients had tumors in the maxilla and in 58 in the mandible. Median age for maxilla, mandible, and other localizations was 45.5, 49, and 23 years, respectively. Age-corrected incidence for osteosarcomas increased after a steep decline for the age cohorts from 20 to 60 years to nearly the same level as the younger patients. The incidence for maxillary lesions showed a steady increase from 0.46 to 1.60 per million over all age ranges; the highest incidence for mandibular lesions was found in the age cohort from 60 to 79 years. In respect to histology, no shifts for age were found, except for Paget’s disease-related osteosarcoma. In older patients, chemotherapy was omitted more often. Overall survival was similar for all age groups, except for extragnatic tumor patients in the age range of 60–79 years.Conclusions. Osteosarcomas have comparable incidences below the age of 20 as compared with ages >60 years. Poorer outcome in older people is likely due to refraining from chemotherapy.

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Comparison of Outcomes of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Older Versus Younger Patients

Blood ◽

10.1182/blood-2020-141966 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-27

Author(s):

Giacomo Adoncecchi ◽

Ambuj Kumar ◽

Rawan Faramand ◽

Hien D. Liu ◽

Farhad Khimani ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Chronic Gvhd ◽

Age Groups ◽

Group Versus ◽

Survival Outcomes ◽

Advisory Committees ◽

Younger Patients ◽

Two Age Groups

Introduction: Previous studies have demonstrated that allogeneic haploidentical (haplo) peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) yields improved progression free survival (PFS) when compared to haplo bone marrow transplant (BMT) with PTCy, attributable to lower relapse without an increase in non-relapse mortality (NRM) (Bashey, et al. JCO. 2017). However, haplo PBSCT results in higher rates of graft-versus-host disease (GVHD) which may negate these benefits in older patients who are more susceptible to transplant related toxicity. Thus, evaluation of the outcomes of haplo PBSCT with PTCy in older patients is warranted. Methods: We retrospectively evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic T-cell replete PBSCT from a haplo donor followed by PTCy-based GVHD prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Myeloablative (n=70, 58%) and reduced intensity (n=51, 42%) conditioning regimens were included. Transplant related outcomes were compared between two age groups: <60 years (n=66) versus >60 years (n=55). Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan-Meier curves and cumulative incidence function curves were also plotted. Results: The median age at the time of transplant was 42 years (range: 20-59) for the younger group and 66 years (range: 61-75) for the older group. The median follow-up was 17 months (range: 2-53) for the entire cohort. Younger patients were more likely to receive myeloablative conditioning (83% versus 27%, p<0.001). Baseline characteristics were otherwise similar. Neutrophil engraftment (>500/uL) by day 30 did not differ significantly between the younger and older group (98% versus 93%, p=0.26). However, the median time to neutrophil engraftment was faster in the younger group versus the older group (16 versus 21 days, p<0.001). Platelet engraftment (>20,000/uL) by day 90 was achieved in 92% in the younger group versus 76% in the older group (p=0.03). The time to platelet engraftment was faster in the younger group: 28 days versus 36 days (p=0.006). At day 100, the cumulative incidence (CuI) of grade II-IV acute GVHD in younger patients was 42% (95% CI 29-61%) and for older patients was 35% (95% CI 22-55%, p=0.82). The CuI for grade III-IV acute GVHD for the younger and the older groups were 8% (95% CI 4-25%) and 15% (95% CI 7-38%, p=0.23), respectively. At 2 years, the CuI of chronic GVHD was 67% (95% CI 55-82%) for younger patients versus 56% (95% CI 38-82%) for older patients (p=0.20). NRM for the younger group and the older group, respectively, was 6% (95% CI 2-16%) versus 19% (95% CI 11-34%) at 100 days and 14% (95% CI 6-30%) versus 22% (95% CI 13-37%) at 2 years (p=0.17). The CuI of relapse at 2 years was not significantly different between the two age groups, with the younger recipients having a CuI of 42% (95% CI 20-60%) and the older group 31% (95% CI 17-56%, p=0.70). The 2-year DFS was similar between the younger and older group, respectively: 51% (95% CI 36-66%) and 53% (95% CI 37-70%, p=0.72). Similarly 2-year overall survival (OS) for the younger group was 59% (95% CI 44-74%), while the older group was 66% (95% CI 52-80%, p=0.92). In multivariate analysis, NRM was superior in the younger group (HR=0.31, 95% 0.12-0.82, p=0.02). Otherwise, age was not associated with engraftment, risk of acute or chronic GVHD, relapse, DFS, or OS. Conclusion: Our results demonstrate that outcomes following allogeneic haplo PBSCT with PTCy in patients >60 years approximate outcomes in patients <60 years. While NRM was inferior in the older patient group, this difference did not result in significant differences in long term OS or DFS. Instead, other variables such as the hematopoietic comorbidity index and the disease risk index were better indicators of survival outcomes. Additionally, these survival outcomes with haplo PBSCT with PTCy appear to be similar to prior published data with haplo BMT with PTCy in older patients (Kasamon, et al. JCO. 2015). Based on this study, haplo PBSCT with PTCy is an appropriate transplant platform for elderly patients. Disclosures Khimani: Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

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Reduced Severe aGVHD and Improved Survival Using Post Transplant Cyclophosphamide/Tacrolimus/Methotrexate Graft Versus Host Disease Prophylaxis in AML Patients Receiving Myeloablative Fractionated Busulfan Conditioning Regimen

Blood ◽

10.1182/blood-2019-125996 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3296-3296

Author(s):

Uday Popat ◽

Rima M. Saliba ◽

Rohtesh S. Mehta ◽

Amanda L. Olson ◽

Julianne Chen ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Similar Proportion ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four day regimen. (Popat et al Lancet Haematology 2018). Subsequently, we added post-transplant cyclophosphamide (PTCy) GVHD prophylaxis to our fractionated regimen with a hypothesis that it will reduce GVHD and improve outcomes. Herein, we report the results of our retrospective analysis comparing outcomes of patients with AML who received fractionated busulfan myeloablative conditioning and PTCy versus standard tacrolimus (Tac) and methotrexate (Mtx) GVHD prophylaxis. Methods: Patients with AML between 18-70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor, who were treated on 4 consecutive protocols using fractionated busulfan were included in the analysis. All patients received two fixed doses of busulfan 80mg/m2 as outpatient either on days -13 and -12, or on days -20 and-13 followed by busulfan on day -6 to -3 dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. Fludarabine ± cladribine were given on day -6 to -3. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and Tac ± mycophenolate mofetil in PTCy cohort (n=53), or standard Tac+ Mtx (n=53). Patients in both the cohorts were matched 1:1 by propensity score. Results: Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 60 (range, 18-70) and 58 (range, 24-70) years, respectively, (P=0.3). Forty-nine percent were in CR, and 30% had comorbidity index >3 in each arm. Similar proportion of patients had ELN adverse risk in both arms (43% vs 40%, respectively P=0.7). The median follow up was 19 months (range, 3-36) in the PTCy and 46 months (range, 14-73) in Tac/Mtx cohort. Overall survival at 2-year was 78% vs 58% (P=0.03), non-relapse mortality was 6% vs 13% (P=0.2), incidence of grade 3-4 acute GVHD at 1-year was 6% vs 19% (P=0.07) and chronic GVHD at 2-year was 10% vs 29% (P=0.03) [Table 1 and figure 1]. The median time to neutrophil engraftment was prolonged by 3 days (15 vs 12 days; P<0.001) and platelet engraftment by 9 days (22 vs 13 days; P<0.001) in the PTCy cohort. Full donor chimerism at day 30 was noted in 79% vs 28% in the PTCy and Tac/Mtx cohorts respectively, (P<0.001). Conclusion: As compared to Tac/Mtx, PTCy-based GVHD prophylaxis not only reduced severe acute GVHD and chronic GVHD, but also improved overall survival in AML patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning. Prospective randomized trial is warranted to validate these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Kite: Honoraria; Pfizer: Honoraria; Amgen: Research Funding; Jazz: Consultancy. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Qazilbash:Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

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Effect of Sirolimus on Immune Reconstitution Following Myeloablative Allogeneic Stem-Cell Transplantation: A Post-Hoc Analysis of a Randomized Controlled Trial Comparing Sirolimus/Tacrolimus with Tacrolimus/Methotrexate (BMT CTN 0402)

Blood ◽

10.1182/blood-2018-99-115662 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2110-2110 ◽

Cited By ~ 1

Author(s):

Mahasweta Gooptu ◽

Haesook T. Kim ◽

Alan Howard ◽

Sung W. Choi ◽

Robert J. Soiffer ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Board Of Directors ◽

Immune Reconstitution ◽

Advisory Committees ◽

Post Hoc Analysis ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Post Hoc

Abstract Introduction: Although allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic neoplasms, one of its limiting toxicities continues to be graft versus host disease, both acute and chronic (aGVHD, cGVHD). Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor which has been found to be effective in GVHD prophylaxis, in combination with calcineurin inhibitors like tacrolimus. The impact of sirolimus on immune reconstitution has not been comprehensively investigated in-vivo thus far. We now present a post-hoc analysis of the randomized study BMT-CTN 0402, examining the effect of sirolimus on immune subsets post-transplant. We further examine the association between different lymphocyte subsets and outcomes post-transplant in each arm. Methods: BMT-CTN 0402 was a randomized trial (n=304) which compared two GVHD prophylaxis regimens, sirolimus/tacrolimus (Sir/Tac) versus tacrolimus/methotrexate (Tac/MTX), in AML/ALL/MDS patients, undergoing myeloablative HLA-matched transplantation. There was no difference in 114-day GVHD free survival (primary end-point) as well as acute or chronic GVHD, relapse or overall survival between arms. 264/304 patients had available samples for the current post-hoc analysis. Blood samples were collected at 1,3, 6, 12 and 24 months post-HCT. Multi-parameter flow cytometry was performed at the project lab (Esoterix Clinical Trials Services) in a blinded fashion, and results were compared between arms. Multivariable Cox regression models, treating each phenotypic parameter as a time dependent variable, were constructed to study impact of reconstitution on clinical outcomes. Results: There were no significant differences in patient and transplant characteristics between the Sir/Tac and Tac/MTX arms in this analysis. Absolute lymphocyte count (ALC), CD3+ and CD4+ counts were significantly decreased in the Sir/Tac arm upto 3 months post-HCT while CD8+ cells recovered even slower (upto 6 months) in this arm (Figure 1, Panels A,B and C). Interestingly there was no difference in the absolute number of regulatory T-cells (Tregs/CD4+ CD25+) between arms at any point post-HCT (Figure 1, Panel D). However the Treg:Tcon ratio was significantly greater in the Sir/Tac arm in the first 3 months post-HCT (Figure 1, Panel E). B-lymphocyte recovery was significantly compromised in the Sir/Tac arm from 1 to 6 months post-HCT (Figure 1, Panel F) while NK cells reconstitution was not affected in the sirolimus arm. In the outcomes analysis, higher numbers of CD3+, CD4+. CD8+ and Tregs were associated with better overall survival. Neither Treg numbers nor Treg:Tcon ratio correlated with GVHD. Conclusion: Sir/Tac has a more profound T-cell suppressive effect than the standard of care combination of Tac/MTX in the early post-transplant period, and particularly compromises recovery of CD8+ T-cells with potential implications in the prevention of aGVHD. Sirolimus when used in-vivo with tacrolimus does not result in increased absolute numbers of Tregs, however it does have a beneficial effect on the Treg:Tcon balance in the first 3 months after transplantation, which may be important in the context of cGVHD prevention. Calcineurin-inhibitor free, sirolimus containing GVHD prophylaxis strategies, incorporating other novel agents, should be investigated further to maximize the favorable effect of sirolimus on Treg:Tcon balance in the post-transplant immune repertoire. Sirolimus significantly compromises B-cell recovery in the first 6 months post-HCT with potential complex effects on cGVHD which merit further study. Acknowledgments: Support for this study was provided by grant #U10HL069294 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute, along with contributions by Wyeth Pharmaceuticals Inc. BMT CTN 0402 biospecimens were obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the above mentioned parties Additional support was provided by the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases for the ancillary study, 'GVHD Prophylaxis - Immune Reconstitution.' Disclosures Soiffer: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Excellent Survival and Immune Reconstitution Following Matched/Mismatched Unrelated and Mismatched Related Transplantation in Adult Patients with Sickle Cell Disease: Updated Results from a Single Center Experience

Blood ◽

10.1182/blood-2019-132113 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2043-2043

Author(s):

Amer Assal ◽

Diane George ◽

Monica Bhatia ◽

Divaya Bhutani ◽

Christian Gordillo ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Unrelated Donor ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cell Counts ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Grade Ii

Introduction: The only cure for sickle cell disease (SCD) is allogeneic hematopoietic stem cell transplant (HSCT) although autologous HSCT of genetically engineered hematopoietic stem cells is promising. Lack of suitable matched related donors (MRD) is a major limitation driving interest in improving outcomes using unrelated donors. While excellent outcomes are achieved with non-myeloablative MRD HSCT in adults (Hsieh et al, 2009 and 2014), results from matched unrelated donor (MUD) HSCT have been limited by excessive graft versus host disease (GVHD) and treatment-related mortality (Shenoy et al, 2016). Here we present updated follow up of our institutional experience using MUD and mismatched unrelated donors (MMUD) in comparison to patients with MRD. Methods: Eligibility for HSCT included frequent pain crises requiring hospitalization and evidence of end-organ damage. Non-myeloablative conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) was used for MRD HSCT (n=7), whereas patients without an MRD were transplanted using MUD, MMUD or haploidentical grafts (n=6) on a previously reported institutional protocol after conditioning with alemtuzumab (54 mg/m2), fludarabine (180 mg/m2), and melphalan (140 mg/m2), using a CD34+ selected graft with CD3+ cell add back. MRD recipients received sirolimus as GVHD prophylaxis. Non-MRD recipients initially received tacrolimus as GVHD prophylaxis (n=1) but subsequently received sirolimus (n=5) due to the first patient developing posterior reversible encephalopathy syndrome (PRES). All grafts were G-CSF mobilized peripheral blood grafts and all patients underwent RBC exchange to achieve Hgb S <30%. Data is reported using n (%) or median (range) and Wilcoxon rank-sum test was used for continuous variables. Results: Median follow up is 21.7 months (range 4.7 - 63.4). Median age for MRD recipients was 28.7 (21.4 - 35.5) years and 22.8 (18.5 - 34.6) for non-MRD recipients. Of note, the MRD group included one patient with a renal allograft from the same donor and another with stage V renal disease awaiting a kidney transplant. All patients where homozygous for hemoglobin S except one who had hemoglobin Sβo -thalassemia in the MRD group, and another heterozygous for hemoglobin S and C in the non-MRD group. Patients in the MRD group received unmanipulated grafts with a median of 14 (6.2 - 16.9) x 10E6 CD34+ cells/kg. Non-MRD recipients received CD34 - selected grafts with a median of 7.8 (4.1 - 15.1) x 10E6 CD34+ cells/kg with 2.2 x 10E5 (0.1 - 2.5) CD3+ cells add back. No growth factors were used post-transplant. All patient engrafted with no cases of graft failure. Median time to engraftment was significantly longer for the MRD group at 25 (22 - 30) vs 19 (13 - 21) days, p=0.003. Two patients in the MRD group developed acute/late acute GVHD (2 grade II), and 3 patients in the non-MRD group (1 grade II, 2 grade III), 2 of which developed in while switching immune suppression due to PRES. All GVHD cases were steroid responsive and resolved. Three patients in the non-MRD group developed PRES and none in the MRD group. There were no cases of treatment related mortality and all patients are alive and free of SCD. As both groups received alemtuzumab, and the non-MRD group received a CD34-selected graft, we examined lymphocyte subset reconstitution at day 100 and 1 year post-HSCT. The most striking difference was in median CD8+ T cell counts at day +100 which were lower in the non-MRD group approaching significance [101 (43 - 2995) vs 6.5 (3 - 2233) cells/uL, p=0.055, for the MRD and non-MRD respectively]. CD8+ T-cell counts were not significantly different at 1 year [402 (184 - 1066) vs 774 (143 - 1002) cells/uL, p<0.99]. Results from other lymphocyte subsets including CD4+ T-cells, NK cells and B cells are shown in table 1 and were not significantly different between the 2 groups. Of note, early donor T-cell chimerism at D100 was not significantly different between MRD and non-MRD groups [27.0 (18.0 - 50.0) % vs 37.5 (3.0 - 80.0) %, p=0.83] whereas at 1-year, MRD group donor T cell chimerism was significantly lower [53.5 (17.0 - 65.0) % vs 82.7 (69 - 90), p=0.01]. Conclusion: We demonstrate excellent outcomes with 100% survival and no graft rejection following matched and mismatched unrelated donor HSCT for adult patients with severe SCD. Larger cohorts are needed to confirm these results and further delineate the impact of T-cell subset reconstitution on early-post transplant complications. Disclosures Assal: Incyte corporation: Consultancy, Research Funding; boston biomedical: Consultancy. Bhatia:BMS: Consultancy; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. Lentzsch:Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy. Reshef:Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding.

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