The Effect of Age and CD34+ Stem Cell Dose on Autologous Hematopoietic Stem Cell Transplantation Outcomes in Multiple Myeloma - Single Institution Experience

Autologous hematopoietic stem cell transplantation (AHSCT) after melphalan (Mel) conditioning has been shown to improve outcomes in patients (pts) with multiple myeloma (MM), including complete response (CR), progression free (PFS) and overall survival (OS). Successful stem cell rescue with adequate number of CD34+ stem cells is thought to be important in achieving these goals post-AHSCT, including reduced platelet (plt) transfusion need, neutrophil engraftment time and previously noted effect on lower cumulative incidence of relapse (CIR). However, there has been some discordance regarding the optimal CD34+ transplantation dose and the effects on outcomes. A retrospective analysis of 508 consecutive MM patients (pts) who underwent AHSCT between 1994-2017 at a single institution was performed to determine the relationship between OS and PFS/CIR at two different CD34+ stem cell infusion dose cutoffs (< 2.5 vs ≥ 2.5 x 106 (mill) CD34+ cells/kg, or < 5.0 vs ≥ 5.0 mill CD34+), an age cutoff (< 65 vs ≥ 65) and a Mel conditioning dose cutoff of 140 mg/m2 vs 200 mg/m2. Multivariate analysis considered high risk MM, defined as either having one of the high risk fluorescent in situ hybridization probes [del17p, t(4;14), t(14;16), t(14;20), gain1q, del1p] or having a complex karyotype (standard risk MM did not contain either), international staging system (ISS) stages I, II and III, and immunomodulatory drug (IMiD)-containing induction (yes/no). Fisher's exact test and the Mann-Whitney test were used to look at the association of CD34+ cutoff groups and patient characteristics. OS was defined as the time from infusion to death from any cause, and was determined by the Kaplan-Meier method; comparisons of survival curves was done using the log-rank test. The CIR was determined using cumulative incidence methods that considered death as a competing event. Gray's test was used to compare CIR curves. Linear regression and Cox regression were used for multivariable analysis. P<0.05 was considered statistically significant. Overall, CD34+ dichotomized at 2.5 or 5.0 mill was not associated with PFS (p=0.25, HR 1.19, CI 0.88-1.62; p=0.99, HR 1.00, CI 0.74-1.35) or OS (p=0.50, HR 1.11, CI 0.82-1.51; p=0.27, HR 0.85, CI 0.63-1.41). When analyzing OS by either age (< 65 vs ≥ 65), Mel conditioning (140 mg/m2 vs 200 mg/m2) or CD34+ infusion cutoffs (< 2.5 vs ≥ 2.5, or < 5.0 vs ≥ 5.0 mill), there was no statistically significant difference. On univariate analysis, the CIR was not statistically different for Mel 140 mg/m2 vs 200 mg/m2 patients at 2.5 mill CD34+ cutoff (p=0.62), but was approaching significance at 5.0 mill cutoff (p=0.054). On univariate analysis, the CIR was not statistically different for patients aged < 65 vs ≥ 65 at 2.5 mill CD34+ cutoff (p=0.92), or 5.0 mill cutoff (p=0.11). On univariate analysis, the CIR was statistically different for CD34+ at 5.0 mill cutoff for patients age ≥ 65 (p=0.01, Figure 1A) and for CD34+ at 5.0 mill cutoff for pts who received Mel140 mg/m2 conditioning (p=0.01, Figure 1B). However, after adjusting for the ISS stage and MM risk in both groups, no difference in CIR was noted (respectively p=0.095, HR: 2.00; 95% CI 0.88, 4.53; p=0.21, HR: 1.77; 95% CI 0.73, 4.29). In a subset analysis for pts ≥ 65 years at the CD34+ 5.0 mill cutoff, mean time in days to neutrophil engraftment on multivariate analysis was shorter for pts who received CD34+ ≥ 5.0 mill compared to < 5.0 mill after adjusting for Mel dose (140 mg/m2 vs 200 mg/m2), ISS stage (I,II vs III), MM risk (standard vs high) and IMiD induction (yes vs no): 11.1 days vs. 12.1 days (p<0.0001). Mean time in days to last platelet infusion on multivariate analysis was also shorter after adjusting for the Mel dose, ISS stage, MM risk and IMiD induction: 7.3 days vs. 10.6 days (p=0.0083). After adjusting for the same variables in multivariate analysis, depth of response at day+100 (CR vs partial response) was not statistically different. Hospitalization duration in days was not significantly affected by either Mel dosing or CD34+ dose. Our single institution experience suggests that there is no significant association between CD34+ stem cell infusion dose at either 2.5 mill or 5.0 mill cutoffs and post-AHSCT outcomes with either Mel dose once controlled for relevant disease specific factors. However, our results do suggest that in pts ≥ 65 years of age, infusing ≥ 5.0 mill CD34+ cells shortens time to neutrophil engraftment and reduces plt transfusion requirements during AHSCT. Disclosures Holstein: Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Lunning:Curis: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Bayer: Consultancy; DAVA: Consultancy; Gilead Sciences, Inc.: Consultancy; Kite: Consultancy; Novartis: Consultancy; OncLive: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy. Armitage:Oncology Analytics: Consultancy; Partner Therapeutics: Consultancy; Samus Therapeutics: Consultancy; Ascentage: Consultancy; Union Pacific: Consultancy; Tesaro bio: Membership on an entity's Board of Directors or advisory committees. Al-Kadhimi:Seattle Genetics: Other: Stocks; Celldex Biotech: Other: Stocks. Vose:Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria; Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Lower Hematopoietic Progenitor Cell Counts and Yields at Subsequent Donations Is Influenced By a Shorter Inter-Donation Interval between the First and Subsequent Mobilizations

Blood ◽

10.1182/blood-2019-123492 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1962-1962

Author(s):

Sandhya R. Panch ◽

Brent R. Logan ◽

Jennifer A. Sees ◽

Bipin N. Savani ◽

Nirali N. Shah ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Time Interval ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Peripheral Blood Cd34 ◽

Cell Counts ◽

Cd34 Cells

Introduction: Approximately 7% of unrelated hematopoietic stem cell (HSC) donors are asked to donate a subsequent time to the same or different recipient. In a recent large CIBMTR study of second time donors, Stroncek et al. incidentally found that second peripheral blood stem cell (PBSC) collections had lower total CD34+ cells, CD34+ cells per liter of whole blood processed, and CD34+ cells per kg donor weight. Based on smaller studies, the time between the two independent PBSC donations (inter-donation interval) as well as donor sex, race and baseline lymphocyte counts appear to influence CD34+ cell yields at subsequent donations. Our objective was to retrospectively evaluate factors contributory to CD34+ cell yields at subsequent PBSC donation amongst NMDP donors. Methods. The study population consisted of filgrastim (G-CSF) mobilized PBSC donors through the NMDP/CIBMTR between 2006 and 2017, with a subsequent donation of the same product. evaluated the impact of inter-donation interval, donor demographics (age, BMI, race, sex, G-CSF dose, year of procedure, need for central line) and changes in complete blood counts (CBC), on the CD34+ cell yields/liter (x106/L) of blood processed at second donation and pre-apheresis (Day 5) peripheral blood CD34+ cell counts/liter (x106/L) at second donation. Linear regression was used to model log cell yields as a function of donor and collection related variables, time between donations, and changes in baseline values from first to second donation. Stepwise model building, along with interactions among significant variables were assessed. The Pearson chi-square test or the Kruskal-Wallis test compared discrete variables or continuous variables, respectively. For multivariate analysis, a significance level of 0.01 was used due to the large number of variables considered. Results: Among 513 PBSC donors who subsequently donated a second PBSC product, clinically relevant decreases in values at the second donation were observed in pre-apheresis CD34+ cells (73.9 vs. 68.6; p=0.03), CD34+cells/L blood processed (32.2 vs. 30.1; p=0.06), and total final CD34+ cell count (x106) (608 vs. 556; p=0.02). Median time interval between first and second PBSC donations was 11.7 months (range: 0.3-128.1). Using the median pre-apheresis peripheral blood CD34+ cell counts from donation 1 as the cut-off for high versus low mobilizers, we found that individuals who were likely to be high or low mobilizers at first donation were also likely to be high or low mobilizers at second donation, respectively (Table 1). This was independent of the inter-donation interval. In multivariate analyses, those with an inter-donation interval of >12 months, demonstrated higher CD34+cells/L blood processed compared to donors donating within a year (mean ratio 1.15, p<0.0001). Change in donor BMI was also a predictor for PBSC yields. If donor BMI decreased at second donation, so did the CD34+cells/L blood processed (0.74, p <0.0001). An average G-CSF dose above 960mcg was also associated with an increase in CD34+cells/L blood processed compared to donors who received less than 960mcg (1.04, p=0.005). (Table 2A). Pre-apheresis peripheral blood CD34+ cells on Day 5 of second donation were also affected by the inter-donation interval, with higher cell counts associated with a longer time interval (>12 months) between donations (1.23, p<0.0001). Further, independent of the inter-donation interval, GCSF doses greater than 960mcg per day associated with higher pre-apheresis CD34+ cells at second donation (1.26, p<0.0001); as was a higher baseline WBC count (>6.9) (1.3, p<0.0001) (Table 2B). Conclusions: In this large retrospective study of second time unrelated PBSC donors, a longer inter-donation interval was confirmed to be associated with better PBSC mobilization and collection. Given hematopoietic stem cell cycling times of 9-12 months in humans, where possible, repeat donors may be chosen based on these intervals to optimize PBSC yields. Changes in BMI are also to be considered while recruiting repeat donors. Some of these parameters may be improved marginally by increasing G-CSF dose within permissible limits. In most instances, however, sub-optimal mobilizers at first donation appear to donate suboptimal numbers of HSC at their subsequent donation. Disclosures Pulsipher: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Bellicum: Consultancy; Amgen: Other: Lecture; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Honoraria. Shaw:Therakos: Other: Speaker Engagement.

Download Full-text

Plerixafor (Mozobil ®)Plus G-CSF Is Effective in Mobilizing Hematopoietic Stem Cells in Patients with Concurrent Thrombocytopenia Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.3229.3229 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3229-3229 ◽

Cited By ~ 1

Author(s):

Ivana N Micallef ◽

Eric Jacobsen ◽

Paul Shaughnessy ◽

Sachin Marulkar ◽

Purvi Mody ◽

...

Keyword(s):

Stem Cell ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Platelet Counts ◽

Cd34 Cells ◽

Low Platelet Count ◽

Equity Ownership

Abstract Abstract 3229 Poster Board III-166 Introduction Low platelet count prior to mobilization is a significant predictive factor for mobilization failure in patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) undergoing autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT; Hosing C, et al, Am J Hematol. 2009). The purpose of this study is to assess the efficacy of HSC mobilization with plerixafor plus G-CSF in patients with concomitant thrombocytopenia undergoing auto-HSCT. Methods Patients who had failed successful HSC collection with any mobilization regimen were remobilized with plerixafor plus G-CSF as part of a compassionate use program (CUP). Mobilization failure was defined as the inability to collect 2 ×106 CD34+ cells/kg or inability to achieve a peripheral blood count of ≥10 CD34+ cells/μl without having undergone apheresis. As part of the CUP, G-CSF (10μg/kg) was administered subcutaneously (SC) every morning for 4 days. Plerixafor (0.24 mg/kg SC) was administered in the evening on Day 4, approximately 11 hours prior to the initiation of apheresis the following day. On Day 5, G-CSF was administered and apheresis was initiated. Plerixafor, G-CSF and apheresis were repeated daily until patients collected the minimum of 2 × 106 CD34+ cells/kg for auto-HSCT. Patients in the CUP with available data on pre-mobilization platelet counts were included in this analysis. While patients with a platelet count <85 × 109/L were excluded from the CUP, some patients received waivers and were included in this analysis. Efficacy of remobilization with plerixafor + G-CSF was evaluated in patients with platelet counts ≤ 100 × 109/L or ≤ 150 × 109/L. Results Of the 833 patients in the plerixafor CUP database, pre-mobilization platelet counts were available for 219 patients (NHL=115, MM=66, HD=20 and other=18.). Of these, 92 patients (NHL=49, MM=25, HD=8 and other=10) had pre-mobilization platelet counts ≤ 150 × 109/L; the median platelet count was 115 × 109/L (range, 50-150). The median age was 60 years (range 20-76) and 60.4% of the patients were male. Fifty-nine patients (64.1%) collected ≥2 × 109 CD34+ cells/kg and 13 patients (14.1%) achieved ≥5 × 106 CD34+ cells/kg. The median CD34+ cell yield was 2.56 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 68.5%. The median time to neutrophil and platelet engraftment was 12 days and 22 days, respectively. Similar results were obtained when efficacy of plerixafor + G-CSF was evaluated in 29 patients with platelet counts ≤ 100 × 109/L (NHL=12, MM=10, HD=3 and other=4). The median platelet count in these patients was 83 × 109/L (range, 50-100). The median age was 59 years (range 23-73) and 60.4% of the patients were male. The minimal and optimal cell dose was achieved in 19(65.5%) and 3(10.3%) patients, respectively. The median CD34+ cell yield was 2.92 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 62.1%. The median time to neutrophil and platelet engraftment was 12 days and 23 days, respectively. Conclusions For patients mobilized with G-CSF alone or chemotherapy ±G-CSF, a low platelet count prior to mobilization is a significant predictor of mobilization failure. These data demonstrate that in patients with thrombocytopenia who have failed prior mobilization attempts, remobilization with plerixafor plus G-CSF allows ∼65% of the patients to collect the minimal cell dose to proceed to transplantation. Thus, in patients predicted or proven to be poor mobilizers, addition of plerixafor may increase stem cell yields. Future studies should investigate the efficacy of plerixafor + G-CSF in front line mobilization in patients with low platelet counts prior to mobilization. Disclosures Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacobsen:Genzyme Corporation: Research Funding. Shaughnessy:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Mody:Genzyme Corporation: Employment, Equity Ownership. van Rhee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Impact of HLA Molecular Mismatch on Haploidentical Hematopoietic Stem Cell Transplantation: A Center for International Blood and Marrow Transplant Research Study

Blood ◽

10.1182/blood-2021-146847 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3917-3917

Author(s):

Jun Zou ◽

Tao Wang ◽

Yung-Tsi Bolon ◽

Shahinaz M. Gadalla ◽

Steven G.E. Marsh ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Hla Class I ◽

Marrow Transplant ◽

Class I ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Blood And Marrow Transplant ◽

Neutrophil Engraftment

Abstract ABSTRACT BACKGROUND The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) being performed has substantially increased in recent years. Single-center studies have previously used in silico algorithms to quantitively measure HLA disparity and shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD) in haplo-HSCT. However, inconsistent results from small studies have made it difficult to understand the full clinical impact of molecular mismatch in haplo-HSCT. OBJECTIVE In the current study, we investigated the potential of the HLA class I and II mismatched eplet (ME) score measured by HLAMatchmaker, as well as ME load at a specific locus to predict outcomes in a registry-based cohort of haplo-HSCT recipients. STUDY DESIGN We analyzed data from patients (n= 1,287) who underwent their first haplo-HSCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome between 2013 and 2017, as reported to the Center for International Blood and Marrow Transplant Research database. ME load at each HLA locus and total Class-I and -II were scored using the HLAMatchmaker module incorporated in HLA Fusion software v4.3, which identifies predicted eplets based on the crystalized HLA molecule models and identifies ME by comparing donor and recipient eplets. RESULTS In the cohort studied, ME scores derived from total HLA Class I or Class II loci or individual HLA loci were not associated with overall survival, disease-free survival, non-relapse mortality, relapse, acute or chronic GVHD (P< .01). An unexpected strong association was identified between total class II ME load in the GVH direction and slower neutrophil engraftment (HR 0.82; 95% CI, 0.75 - 0.91; P < .0001) and platelet engraftment (HR 0.80; 95% CI, 0.72 - 0.88; P < .0001). This was likely attributable to ME load at the HLA-DRB1 locus, which was similarly associated with slower neutrophil engraftment (HR 0.82; 95% CI, 0.73 - 0.92; P = .001) and slower platelet engraftment (HR 0.76; 95% CI, 0.70 - 0.84; P < .0001). Additional analyses suggested that this effect is attributable to matched vs. mismatched in the GVH direction and not to ME load, as there was no dose effect identified. CONCLUSION These findings contradict those of prior relatively small studies reporting that ME load, as quantified by HLAMatchmaker, was associated with haplo-HSCT outcomes. As the study failed to demonstrate the predictive value of ME from HLA molecules for major clinical outcomes, other molecular mismatch algorithms in haplo-HSCT settings should be tested. Disclosures Lee: Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Janssen: Other; Takeda: Research Funding; Syndax: Research Funding; AstraZeneca: Research Funding; Kadmon: Research Funding; Amgen: Research Funding.

Download Full-text

Effect of Daratumumab-Containing Induction on CD34+ Hematopoietic Stem Cells before Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood-2021-150360 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2764-2764

Author(s):

Ondrej Venglar ◽

Tereza Sevcikova ◽

Anjana Anilkumar Sithara ◽

Veronika Kapustova ◽

Jan Vrana ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Cd34 Cells ◽

Fcm Analysis ◽

D 12

Abstract Introduction: Daratumumab (Dara) is an anti-CD38 monoclonal antibody representing a novel treatment agent for multiple myeloma (MM). Nonetheless, several studies have reported a Dara-related impairment of CD34+ hematopoietic stem cell (HSC) mobilization and post-autologous stem cell transplantation (ASCT) complications, including low yields of mobilized HSCs and delayed neutrophil engraftment. Impact of Dara on the mobilization process and HSCs remains poorly understood even though sufficient yields of CD34+ cells are necessary for a successful ASCT and subsequent patient recovery. Aims: To compare the effect of the Dara-containing (Dara-Bortezomib-Dexamethasone [D-VCd]) and conventional (Bortezomib-Thalidomide-Dexamethasone [VTd]) therapy on CD34+ HSCs. Methods: Transplant eligible MM patients were treated with D-VCd or VTd induction regimen followed by a cyclophosphamide + G-CSF mobilization and a high-dose melphalan D -1 before ASCT. Flow cytometry (FCM) screening of CD34+ subsets was performed in the bone marrow (BM) or apheresis product (AP) at three consecutive time points: 1) diagnostic BM (DG), 2) mobilization AP (MOB), 3) a day prior ASCT BM (D-1). Furthermore, RNA sequencing (RNAseq) of sorted CD34+ cells was performed on total RNA with ribo-depletion protocol in AP after the induction. D-VCd samples had lower RNA yields thus the D-VCd or VTd groups were processed as independent batches. Results: Clinical data revealed no significant differences in mobilization (p >0.050) likely due to a small cohort sizes (D-VCd n=5 vs VTd n=9), though a trend towards worse performance in D-VCd was observed. Median CD34+ cell yield was 3.08 vs 10.56 x 10 6/kg. Platelet recovery of >20x10 9/L was D+14 vs D+12 (range: 11-18 vs 10-16). Neutrophil recovery of >0.5x10 9/L was D+12 in both groups (range: 11-17 vs 11-12). In FCM analysis, DG (n=14), MOB D-VCd (n=5) vs VTd (n=9), D-1 D-VCd (n=7) vs VTd (n=15) were compared. CD34+ frequency (Fig. 1A) difference in MOB D-VCd vs VTd was insignificant (median: 1.15% vs 1.89%), whereas CD34+ fraction dropped in D-1 D-VCd (median: 0.52% vs 0.72%, p=0.027), albeit there was no significant reduction in D-1 D-VCd vs initial DG (median: 0.52% vs 0.45%). Differences in the distribution of certain HSC subsets were detected in the CD34+ pool (Fig. 1B-E). Frequency of multipotent progenitors (MPPs) (Fig. 1B) was increased in MOB D-VCd (median: 82.1% vs 66.2%, p=0.004). Frequency of lympho-myeloid-primed progenitor + granulocyte-monocyte progenitor (LMPP+GMP) (Fig. 1C) subset was reduced in D-VCd in both MOB (median: 1.7% vs 16.9%, p=0.042) and D-1 (median: 5.3% vs 14.0%; p=0.026). Erythro-myeloid progenitors (EMPs) (Fig. 1D) were reduced in MOB D-VCd (median: 10.7% vs 19.5%, p=0.042), while the frequency of EMPs increased in D-1 D-VCd (median: 20.8% vs 12.4%, p=0.045). No considerable differences were found in the expression of adhesion molecules CD44/HCAM or CD184/CXCR4. CD38 was strongly diminished in the whole D-VCd CD34+ fraction of MOB and D-1. To understand whether the differences in the mobilization efficacy after D-VCd induction were reflected in the expression profile of mobilized CD34+ cells, differential expression analysis was performed. Overall 133 significantly deregulated genes (p<0.05; log fold change >(-)1) between cohorts (D-VCd n=5 vs VTd n=5) were revealed (Fig. 2). Pathway analysis showed cellular response and localization as the most deregulated categories. The list of deregulated genes contained 25% of non-coding RNAs, some of which were linked to a protein localization in the cell (RN7SL1/2). The expression of adhesion molecules was inspected independently. Out of 59 HSC hallmark genes, only 8 were significantly altered in D-VCd. Interestingly, the main homing molecule CXCR4 seemed to be downregulated in D-VCd, while integrins A3 and B4 were upregulated. Conclusions: Despite the limited cohort sizes, a prospective trend of delayed neutrophil and platelet recovery was observed after D-VCd therapy. FCM analysis revealed a significant reduction of CD34+ subsets responsible, among others, for a reconstitution of neutrophils and megakaryocytes. A strong signal in transcriptome data which would potentially explain differential mobilization in D-VCd cohort was not detected, nevertheless, several genes with adhesive/homing and stem cell differentiation function were indeed altered. The results warrant further investigation. Figure 1 Figure 1. Disclosures Hajek: BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Acceptable Toxicity and Good Hematological and Renal Responses after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency at Transplant: A Prospective SFGM-TC Observational Study

Blood ◽

10.1182/blood-2020-140713 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 38-39 ◽

Cited By ~ 1

Author(s):

Laurent Garderet ◽

Hafida Ouldjeriouat ◽

Mohamed-Amine Bekadja ◽

Elisabeth Daguenet ◽

Laure Vincent ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Function ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Median Number ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cd34 Cells

Background: High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in multiple myeloma (MM) patients as upfront and salvage therapy. However, the safety and efficacy of ASCT in patients with renal insufficiency (RI) is controversial, which have led to an inconsistent arbitrary cut-off for creatinine clearance (CrCl) for performing ASCT. Here we analyzed prospectively the outcomes of MM patients with severe RI who underwent ASCT. Methods: We enrolled prospectively 50 newly diagnosed MM patients who had a serum CrCl of <40 mL/min at the time of ASCT and an age of up to 65 years. They all received bortezomib-based induction therapy and had achieved at least a partial response before proceeding to ASCT. The recommended dose of melphalan was 140 mg/m2 and it was advised to infuse at least 3 x106/kg autologous CD34+ cells. Consolidation/maintenance post-ASCT was according to the physician's choice. The primary endpoint was transplant related mortality. Results: The patients characteristics at enrollment are given in Table 1. We focused on 44 patients who were beyond 3 months post-ASCT. Light chain MM was frequent (12%), 10% had high risk cytogenetics, 36% increased serum LDH and 10% extramedullary disease. Induction chemotherapies included bortezomib plus IMiDs in 25/44 patients with ≥2 lines of chemotherapy in 12/44. The pre-transplant disease status was sCR in =5%, CR in =15%, VGPR in =39%, and PR in =41% of patients. The number of days of cytapheresis was 2 or less in 95% of cases and the median number of CD34+ cells collected was 3.3 x 106 (1.3-9.5). The median time from diagnosis to ASCT was 175 days (103-307). HDM was 140 mg/m2 in 42/44 patients and 200 mg/m2 in 2/44. All, except two, received consolidation post ASCT (34% missing) and 52% had maintenance therapy (all lenalidomide except two receiving bortezomib) and 7% had no maintenance (41% pending). Toxicity: We observed one death during the first 100 days post-ASCT, secondary to a septic shock on day 42. The median time to neutrophil engraftment was 12 days (9-68) and to platelet engraftment 13 days (10-70). Among patients receiving RBC transfusions (75%) and platelet transfusions (84%), the median number of RBC transfusions was 3 (1-6) and that of platelet transfusions was 3 (1-10). Response: Nine patients (70%) achieved dialysis independence from the time of diagnosis: 13 patients were on dialysis at diagnosis, 5 at the time of ASCT and 4 three months post-ASCT. Renal function improved post-ASCT in 34% of patients, 14% moving from a CrCl of <40 mL/min to 60 mL/min and 20% to above 60 mL/min. No patient experienced worsened renal function following ASCT. At 100 days post-ASCT, the hematological response had improved in 49% of patients, from PR to VGPR (18%), from PR to CR/sCR (11%) and from VGPR to CR/sCR (20%). The best response obtained was 5% PR, 34% VGPR, 47% CR and 11% sCR with one patient relapsing. Conclusions: In this preliminary analysis, HDM with ASCT proved to be safe and effective in MM patients with RI at transplant. We observed one death among 44 patients within the first 3 months post-ASCT. A more detailed report of the toxicity will be presented during the meeting along with the survival. Disclosures Vincent: takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Mohty:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Karlin:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Morel:Janssen: Honoraria. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding.

Download Full-text

First Report of Non-Genotoxic Conditioning with JSP191 (anti-CD117) and Hematopoietic Stem Cell Transplantation in a Newly Diagnosed Patient with Severe Combined Immune Deficiency

Blood ◽

10.1182/blood-2020-137762 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-10

Author(s):

Rajni Agarwal ◽

Kenneth I. Weinberg ◽

Hye-Sook Kwon ◽

Anne Le ◽

Janel R Long-Boyle ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Board Of Directors ◽

B Lymphocytes ◽

Hematopoietic Stem Cell ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cd34 Cells

Successful hematopoietic stem cell transplantation (HSCT) requires vacating recipient hematopoietic stem cell (HSC) niches in the bone marrow to permit donor HSC engraftment that can provide life-long hematopoietic and immune function. Currently, HSCT in SCID relies on DNA damaging chemotherapy to eliminate recipient HSC and achieve niche clearance. We have pursued a non-toxic approach to target and deplete HSC using a humanized monoclonal antibody, JSP191, that binds human CD117 (c-Kit). We previously showed the safety and successful HSC engraftment in a Phase 1 trial of the first 6 patients with severe combined immunodeficiency (SCID), who underwent a second transplant because of HSC engraftment failure and poor immunity after their first transplantation. In these re-transplant patients even a low level of stringently measured myeloid chimerism resulted in significant and sustained generation of naive T cells and clinical improvement. Based on these results, the study of JSP191 (NCT#02963064)has opened a cohort of newly diagnosed infants with SCID. Here we report data from the first patient in this cohort, a SCIDX1 patient who received a primary HSCT with haploidentical CD34+ cells after conditioning with JSP 191. The patient had a c.270-15A>G variant in the IL2RG gene, which is predicted to cause a null phenotype. Besides a T- B+ NK- phenotype typical of SCIDX1 including dysfunctional B cells, the patient had anemia and intermittent neutropenia and thrombocytopenia. Despite evidence of maternal T cell engraftment, the patient had no clinical graft-versus-host disease (GVHD). The patient was initially enrolled in a trial of lentiviral gene therapy, but harvested bone marrow cells died in vitro during transduction and culture. The patient also mobilized poorly with G-CSF/Plerixafor. Further investigation revealed heterozygosity for loss-of-function mutations in two genes involved in DNA repair, BRCA1 and RAD51; Diepoxybutane (DEB) breakage study showed greater than normal pathologic chromosomal breaks, but less than that seen in Fanconi anemia. Because of concern for possible hypersensitivity to alkylating agent-based conditioning, the patient was referred for transplant with JSP191 conditioning. The patient received a CD34+ peripheral blood HSCT from his father after conditioning with 0.3 mg/kg of JSP 191 antibody intravenously over an hour on Day -8 and rATG (Thymoglobulin) on Day -5, -4, -3 and -2 (3.5 mg/kg total) to prevent rejection by the maternal T cells. The cryopreserved donor CD34+ cells were administered after sufficient clearance of the JSP191 serum level. The antibody infusion was well tolerated without toxicity, and the post-transplant course was uneventful without acute toxicities or GVHD. As a surrogate marker for HSC engraftment, CD15+ myeloid cells from peripheral blood were stringently sorted by flow cytometry and donor levels were quantified by short-tandem repeat (STR) analysis. Progressive levels of myeloid engraftment were observed beginning at Week 4. The level of donor chimerism at 12 weeks was 8% in the sorted CD15+ blood cells, and a marrow aspirate showed 25% donor CD34+ cells. By 3 months pre-existing abnormal CD19-CD20+ host B lymphocytes were significantly reduced, and CD19+ donor-derived B lymphocytes were emerging. At 2 months, CD4+ recent thymic emigrant and naïve T lymphocytes were observed, and by 3 months, overall T and NK lymphocyte numbers were 390/uL and 117/uL, respectively. Normal blastogenic responses to the T cell mitogen PHA were observed at 3 months. These first-in-class results provide proof of concept of the safety and efficacy of the use of JSP191 antibody to clear host marrow niche space to enable sufficient donor HSC engraftment and immune reconstitution as primary therapy of SCID. Non-genotoxic conditioning with JSP191 may replace conventional conditioning for newly diagnosed infants with SCID, thereby avoiding toxicities of chemotherapy. Disclosures Kohn: Allogene Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Patents & Royalties, Research Funding. De Oliveira:Orchard Therapeutics: Research Funding; bluebird bio, Inc.: Research Funding. Czechowicz:Rocket Pharmaceuticals, Inc.: Research Funding. Brown:Merck: Membership on an entity's Board of Directors or advisory committees; Ansun: Membership on an entity's Board of Directors or advisory committees; Cidara: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Cellerant Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Download Full-text

A Comparison of Chemotherapy + G-CSF Versus Plerixafor (Mozobil®) + G-CSF for Stem Cell Mobilization In Patients with Multiple Myeloma Treated with Lenalidomide

Blood ◽

10.1182/blood.v116.21.2258.2258 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2258-2258

Author(s):

Tomer M Mark ◽

Adriana C Rossi ◽

Roger N Pearse ◽

Morton Coleman ◽

David Bernstein ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Yield ◽

High Dose ◽

Advisory Committees ◽

Cd34 Cells ◽

Stem Cell Collection

Abstract Abstract 2258 Background: Prior use of lenalidomide beyond 6 cycles of therapy in the treatment of multiple myeloma (MM) has been shown to negatively impact stem cell yield, but this phenomenon can be overcome with the addition of high-dose cyclophosphamide to standard G-CSF mobilization. We hypothesized that the use of plerixafor (Mozobil®) would compare similarly to chemotherapy in rescuing the ability to collect stem cells in lenalidomide-treated myeloma. Methods: We performed a retrospective study comparing the efficacy of plerixafor + G-CSF mobilization (PG) to chemotherapy + G-CSF (CG) (either high-dose cyclophosphamide at 3g/m2 or DCEP [4-day infusional dexamethasone/ cyclophosphamide/ etoposide/cisplatin]) in 49 consecutive stem cell collection attempts in patients with MM exposed to prior lenalidomide. The primary endpoint was the ability to collect sufficient stem cells for at least two transplants (minimum 5×106 CD34+ cells/kg), comparing results in terms of total exposure to lenalidomide and time elapsed from lenalidomide exposure until the mobilization attempt. The secondary endpoint was number of apheresis days required to meet collection goal. Resilts: Twenty-four patients underwent PG mobilization and twenty-five with CG (21 with G-CSF + cyclophosphamide, 4 with G-CSF+DCEP). The two groups did not differ in terms of total amount of lenalidomide exposure: median number of lenalidomide cycles for patients mobilized with PG was 6.5 (range 1.2–86.6), vs. 6 (range 2–21.6), for patients mobilized with CG (P = 0.663). The median time between mobilization and last lenalidomide dose was also similar between the two groups: 57.5 (range 12–462) days for PG vs. 154 (range 27–805) days for CG (P = 0.101). There was an equivalent rate of successful collection of 100% for PG and 96% for CG, P = 0.322. One patient failed collection in the CG group due to emergent hospitalization for septic shock during a period of neutropenia; no patient collected with PG had a serious adverse event that interrupted the collection process. Stem cell yield did not differ between the two arms (13.9 vs. 18.8 × 106 million CD34+ cells/kg for PG vs. CG respectively, P = 0.083). Average time to collection goal was also equal, with a median of time of 1 day required in both groups, (range 1–2 days for PG, 1–5 days for CG, P = 0.073). There was no relationship between amount of lenalidomide exposure and stem cell yield with either PG (P = 0.243) or CG (P = 0.867). Conclusion: A plerixafor + G-CSF mobilization schedule is equivalent in efficacy to chemotherapy + G-CSF in obtaining adequate numbers of stem cells for two autologous stem cell transplants in patients with MM exposed to lenalidomide; however, PG may be a less toxic approach than chemomobilization. Number of lenalidomide cycles has no impact on chances of stem cell collection success using either method. Disclosures: Mark: Celgene Corp: Speakers Bureau; Millenium Corp: Speakers Bureau. Zafar: Celgene Corp: Speakers Bureau. Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding.

Download Full-text

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.

Download Full-text

Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽

10.1182/blood.v128.22.3180.3180 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3180-3180

Author(s):

Felix Lopez-Cadenas ◽

Blanca Xicoy ◽

Silvia Rojas P ◽

Kaivers Jennifer ◽

Ulrich Germing ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Univariate Analysis ◽

Rank Test ◽

Advisory Committees ◽

Disease Evolution ◽

Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

Download Full-text