Proteasome Inhibitor Treatment in Multiple Myeloma Can Mobilize Hematopoietic Stem Cells in the Absence of G-CSF

Abstract Introduction Proteasome inhibitor (PI) use in patients (pts) with multiple myeloma (MM) has been associated with increased hematopoietic stem/progenitor cell (HSPC) collection yields in both induction and autologous stem cell collection settings (Niesvizky et al., 2013). Animal models have confirmed this observation (Ghobadi et al., 2012). The mechanism remains unclear, but there is suggestion PI treatment affects pathways associated with HSPC anchoring and migration (Niesvizky et al., 2013). The effect of PIs on HSPC migration in the absence of filgastrim (G-CSF) stimulation remains unknown. We sought to characterize the molecular mechanisms of HSPC mobilization in a cohort of pts undergoing active PI treatment. Methods MM pts undergoing treatment with PIs were consented to obtain peripheral blood (PB) under IRB approval. Pts were eligible if they had symptomatic MM and were undergoing treatment with a PI. Pts receiving alkylating chemotherapy (such as cyclophosphamide) in combination with a PI were excluded. Pts were enrolled on the first day of a new cycle containing a PI. PB was drawn prior to administration of the PI (T0) and just prior to the next dose of PI, 24 or 72 hours later (T1), depending on whether the pt was receiving carfilzomib or bortezomib, respectively. PB mononuclear cells were collected and purified with Ficoll-Paque, viably frozen in CS-10 freezing medium and stored in liquid nitrogen. Serum samples were collected after a 1:2 dilution with PBS and stored at -80oF. Cells were later thawed to perform multiparameter flow cytometry and colony forming unit (CFU) assays. Multiparameter flow cytometry was performed using a BD LSR-II and analyzed using FloJo V9.0 software. Cells were gated on CD45dim SSC-lo characteristics. HSPCs were defined as CD34+/CD133+. Pts were stratified into 3 groups (>2, 1-2, <1) based on fold change in peripheral HSPCs from baseline T0. Expression of surface markers including CD38, CD184, CD202b, CD25, CD90 and CD31 within the HSPC population, were analyzed. Serum protein concentrations were analyzed using ELISAs. Results Twenty-three pts consented and collected at the 2 prespecified time points. Six pts (26%) increased the percentage of peripheral HSPCs>2 fold. Nine (39%) and 8 (35%) pts increased the percentage of HSPCs 1-2 fold and <1 fold over T0 percentage, respectively. There were no statistical differences within the 3 groups, in baseline characteristics, prior chemotherapy, use of IMIDs, or radiation exposure history. There was a significant positive correlation between peripheral HSPC fold change and CFU formation p=0.003 indicating the mobilized HSPC population’s capacity to form progeny. Furthermore, there was a significant negative correlation between fold change of HSPCs and CD90 expression on CD34+ CD133+ CD38- stem cell populations at T1 p=0.032. To determine changes in serum proteins as a result of PI treatment that could contribute to HSPC mobilization we evaluated TGF-ß levels in 13 pt plasma samples. Two pts from the>2fold group were available and revealed TGF-ß levels increase 67.24 pg/mL compared to a decrease of 17.67 pg/mL in 5 pts in the <1fold group trending towards significance p=0.094. Baseline levels of TGF-ß in the two groups,>2fold and <1fold were 18.1 pg/mL and 30.1 pg/mL respectively, which was not significant. Discussion Observations have noted increased HSPC yields in animal models and MM pts after treatment with PIs in both induction and mobilizing regimens (Ghobadi et al., 2012; Niesvizky et al., 2013). Here we demonstrate that treatment with PIs is associated with increases in peripheral HSPC percentages in approximately 2/3 of MM pts despite the lack of concurrent G-CSF. Decreased CD90 has previously been observed in peripherally mobilized HSPC products and, similar to TGF-ß, plays a role in regulation of Rhokinase GTPase pathways known to affect migration and adherence of many different cell types (Tsuchiya et al., 1997; Kim et al., 2006; Wen et al., 2013; Kim et al., 2014). Our study shows a correlation between decreased CD90 expression and fold increase of peripheral HSPCs. We also found an increase in TGF-ß serum levels after treatment in the>2fold group compared to the <1fold group, which may approach statistical significance with more sampling. These findings may help understand the failure to collect adequate HSPCs in a subset of MM pts and could highlight new pathways to disrupt and improve HSPC mobilization regimens. Disclosures Niesvizky: Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Research Funding, Speakers Bureau. Mark:Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau.

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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.

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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.

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Large Granular Lymphocytosis and Its Impact on Long Term Clinical Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation: 14-Year Follow-up Data

Blood ◽

10.1182/blood-2019-128750 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2019-2019

Author(s):

Guldane Cengiz Seval ◽

Atilla Uslu ◽

Ekin Kircali ◽

Sinem Civriz Bozdag ◽

Klara Dalva ◽

...

Keyword(s):

Flow Cytometry ◽

Stem Cell ◽

T Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Support Research

Introduction: Several studies have attempted to describe the characteristics associated with large granular lymphocytosis (LGL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its clinical significance. However the clinical features of LGL lymphocytosis in the allo-HSCT setting is still sparse. The current study represents a detailed review of 667 patients transplanted in a single center with the objective to define the incidence of LGL lymphocytosis, to identify associations with transplant-related clinical parameters and to assess the impact on transplant related outcomes. Patients and Methods: During a 14-year follow up period (2005-2017) in this unicentric cohort study, we identified 19 patients (2.8%) with a significant LGL lymphocytosis, among 667 consecutive adult patients who underwent allo-HSCT. LGL lymphocytosis was defined as the presence of at least two of the following criteria: (1) sustained lymphocytosis above 3.0x109/L observed in at least three consecutive determinations over a time frame of 2-3 months, (2) predominance (that is, >30%) of LGLs in the peripheral blood, (3) confirmation of clonality by T-cell receptor analysis using PCR. Flow cytometry analyses were performed using the flow cytometry system FACSCalibur (BD Biosciences, San Jose, CA). The immunophenotyping of the lymphocytes included the following antibody panel: CD2, CD3, CD4, CD5, CD7, CD8, CD16, CD25, CD30, CD56, CD57, HLA-DR, TCRab, and TCRgd. T-LGL expansion was defined as an abnormal T cell population type CD31, CD81, or CD41, with expression of at least 1 of the NK markers (CD16, CD57, or CD56), and with presence of LGLs in peripheral blood films. Results: A total of 19 (Female/ male: 10 [52.6 %]/ 9 [47.4 %]) patients included into the study met the morphological criteria for LGL lymphocytosis. The median age of the patients was 46 years (range, 18- 62 years). The majority of the patients (64.7 %) had the diagnosis of acute myeloid leukemia. The stem cell source was peripheral blood stem cells (PBSC) in 15 patients (88.2 %) and most of the patients underwent an allo-HSCT with a MAC (n= 13) regimen at a median of 25.1 months from allo-HSCT. The median onset of LGL lymphocytosis was 11.5 (2.1- 55.7) months and median lymphocyte count at the time of diagnosis of LGL lymphocytosis was 5400/ mL (5170- 8700/ mL). None of the patient showed cytopenia, palpable splenomegaly, and none of them had typical signs or symptoms of an autoimmune disease. In addition; GvHD, viral infections, disease relapse and loss of donor chimerism were excluded during lymphocytosis. Samples from 19 patients were phenotyped by flow cytometry. These studies confirmed a T cell phenotype of LGLs in the majority of patients (n=12). Two patients presented with LGLs consistent with NK cells and seven showed properties of a mixed NK/T-cell lineage. A monoclonal LGL population of T-cell origin was identified in eight (42.1%) of these patients. With a median follow-up of 12.2 months none of the patients demonstrating increased LGL values has progressed to LGL leukemia or any other lymphoproliferative disorder. Four patients experienced cutaneous acute GVHD followed by a progressive chronic GVHD. Two patient developed a grade II acute cutaneous GVHD which rapidly responded to steroids in addition to cyclosporin A. Five patients had de novo chronic GVHD. In subgroup analysis, we compared the OS of monoclonal and oligoclonal LGL lymphocytosis and 1-year-OS was longer but non-significantly in monoclonal LGL lymphocytosis group; 75% ± 1.6% vs. 44.4% ± 2.2%, respectively (p= 0.21) (Figure). Median PFS was 28.8 months in oligoclonal LGL lymphocytosis group and 8.3 months in monoclonal LGL lymphocytosis group but the number of patients in this group does not provide enough statistical power to confirm whether the differences in PFS were statistically significant (p= 0.3). At the time of this report, three patients have died. The primary cause of death was relapse of the primary disease in one of the patients, whereas 2 patients died of TRM (10.5%). Discussion: In conclusion, we observed LGL lymphocytosis in 2.8 % of a large cohort of post allo-HSCT survivors. Our data indicate that, even if monoclonal, post-transplantation LGL expansion may be considered as an expression of chronic stimulation triggered by allo-HSCT rather than the result of a malignant transformation. Disclosures Özcan: Amgen: Honoraria, Other: Travel support; BMS: Other: Travel support; Jazz: Other: Travel support; Sanofi: Other: Travel support; Bayer: Research Funding; Novartis: Research Funding; Roche: Other: Travel support, Research Funding; Archigen: Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; Abdi Ibrahim: Other: Travel support; MSD: Research Funding; AbbVie: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding; Celgene Corporation: Research Funding, Travel support. Ilhan:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Beksac:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Melphalan-Based Autologous Transplantation in the Octogenarian Multiple Myeloma Patient Population

Blood ◽

10.1182/blood-2018-99-110241 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4608-4608 ◽

Cited By ~ 2

Author(s):

Neeraj Y Saini ◽

Romil Patel ◽

Ankur Varma ◽

Qaiser Bashir ◽

Ruby Delgado ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Advisory Committees ◽

Hematopoietic Stem

Abstract Abstract: Background: Upfront autologous hematopoietic stem cell transplantation (auto-HCT) combined with novel anti-myeloma drugs is considered the standard of care for transplant-eligible patients with multiple myeloma (MM). However, this treatment is generally avoided in older patients due to concerns about toxicity. MM is primarily a disease of the elderly, with >35% patients being older than 70 years of age at diagnosis. We have previously reported on the role of auto-HCT in MM patients >70 years1. In this study, we evaluate the safety and feasibility of auto-HCT in patients ≥80 years who received auto-HCT at our institution. Methods: We retrospectively reviewed the outcomes of MM patients with age ≥80 years who underwent auto-HCT between January, 2007, and June, 2018. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of auto-HCT to the last follow up or the censored date. Kaplan-Meier method was used to estimate PFS and OS. Results: Between January, 2013, and December, 2017, out of a total of 1465 MM patients referred for evaluation for auto-HCT at our institution, only 10(0.68%) were of age ≥80 years. Also, between January, 2016, and June, 2018, a total of 210 MM patients with age ≥80 years were treated at our institution, and only 3(0.14%) underwent auto-HCT. Overall among 1740 patients with MM who received an auto-HCT at our institution between the beginning of 2007 to June, 2018, 9(0.5%) patients were ≥ 80 years of age (range 80-83). Table 1 summarizes the patient characteristics of these nine patients. All patients had an ECOG performance status of either 0 or 1. The median hematopoietic stem cell transplant - comorbidity index for the cohort was 3 (range, 0-5). Eight (89%) patients were in first remission, and 1 (11%) patient had relapsed disease at auto-HCT. All patients received melphalan at a reduced dose of 140 mg/m2 as the conditioning regimen. Eight patients (89%) received maintenance therapy with lenalidomide. The median follow-up from auto-HCT was 18 months (range 0.5 - 50 months). No (0%) patient died within 100 days of auto-HCT. Out of 8 evaluable patients, 4 (50%) achieved a complete response, 2 (25%) very-good partial, and 2 (25%) achieved a partial response with an overall response rate of 100%. Eight (89%) patients were alive until the last follow-up. Median PFS was 31.5 months, while the median OS has not been reached (Fig1). 2-yr PFS and OS were 62.5% and 75% respectively. One patient died 22 months post-transplant due to non-transplant related cause. Conclusions: In selected MM patients ≥80 years old, auto-HCT was feasible, with 0% TRM, 100% response rate, and 2-year OS of 75%. Almost 90% of these patients went on to receive maintenance therapy. References: Qazilbash, M. H. et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. Bone Marrow Transplantation39, 279-283 (2007). Disclosures Shpall: Affirmed GmbH: Research Funding. Thomas:Celgene: Research Funding; Array Pharma: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Orlowski:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

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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.

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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.

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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.

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Multiple Myeloma In Complete Remission After Autologous Stem Cell Transplantation: Impact of Bone Marrow Plasma Cell Assessment by Conventional Morphology on Disease Progression

Blood ◽

10.1182/blood.v116.21.2946.2946 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2946-2946

Author(s):

Carlos Fernández de Larrea ◽

Natalia Tovar ◽

María Rozman ◽

Laura Rosiñol ◽

Juan I. Aróstegui ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stem Cell ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Bone Marrow Aspirate ◽

Advisory Committees ◽

Bone Marrow Plasma ◽

Serum And Urine

Abstract Abstract 2946 Background: The achievement of complete remission (CR) is the crucial step for a long-lasting response and prolonged survival after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). The European Group for Blood and Marrow Transplantation (EBMT) criteria for CR include the negativity of serum and urine immunofixation (IFE) and less than 5% of bone marrow plasma cells (BMPCs). Additionally, the International Myeloma Working Group (IMWG) has even proposed a stringent CR category, which requires to rule out the clonal nature of the BMPCs. However, few studies have addressed this issue in patients with MM and negative IFE. The aim of the present study was to determine the impact of plasma cell count in the bone marrow aspirate on the long-term outcome of patients with MM with negative IFE after ASCT. Methods: Thirty-five patients (16M/19F; median age at ASCT 55 years, range 26–68) with MM who underwent ASCT from March 1994 to December 2008, were studied. All patients had achieved a negative serum and urine IFE after high dose therapy with melphalan-based regimens. Bone marrow aspirate was performed when negative serum and urine IFE was achieved and at least three months from ASCT (median 3.24 months). The analysis was based on microscopic revision for May-Grünwald-Giemsa stained bone marrow smears performed according to standard procedures. BMPC percentage was calculated independently by two observers counting 500 bone marrow total nucleated cells in random areas from two different slides (1000 cells on each patient). Results: Median BMPCs percentage was 0.8 (range 0.1–5.8). Only two patients had more than 3% BPMCs. These results are in contrast with a recent report from the Mayo Clinic group, where 14% of the patients with MM and negative IFE had 5% or more BMPCs. In univariate Cox-model regression analysis, the number of BMPCs significantly correlated with progression-free survival (PFS)(p=0.021) with no impact on overall survival (OS)(p=0.92). This statistical significance on PFS was retained in the multivariate analysis, when baseline prognostic factors such as age, hemoglobin level, serum creatinine, β2-microglobulin and Durie-Salmon stage were added to the model (p=0.003). To establish the best predictive cut-off for progression and survival, a receptor-operator curve (ROC) analysis was developed. It showed the value of 1.5% BMPCs, with a sensitivity of 53%, specificity of 90% and area under the curve of 0.66 for predicting progression. Ten patients had more than 1.5% BMPC, and 25 equal or less than 1.5% BMPC. Median PFS was 8.5 years (CI 95% 2.6 to 14.3) and was not reached in patients with ≤1.5% BMPCs versus 3.1 years in patients with >1.5% BMPCs, with a hazard ratio probability to progression of 3.02 (CI 95% 1.18 to 9.71)(p=0.016) in the group with more than 1.5% of BMPCs (Figure 1). Median OS was not reached in patients with ≤1.5% compared with a median of 9.7 years in those with more than 1.5% BMPCs (p=0.195) (Figure 2). It is likely that serological CR with very low percentage of BMPCs (i.e. ≤1.5%) is equivalent to negative MRD assessed by MFC or molecular studies. In fact, all 8 patients in continued CR between 9 and 16 years beyond ASCT (“operational cures”) are in the group with ≤1.5% BMPCs, while all patients in the group with >1.5% BPMC have relapsed within the first 9 years from ASCT (Figure 1). Conclusion: The percentage of BMPCs in patients with MM in CR after ASCT is a strong predictor of progression. Bone marrow morphology examination is an easy, inexpensive, and non-time consuming test and it should be the first step in the estimation of the residual tumor mass in patients with MM in CR after ASCT. Disclosures: Rosiñol: Janssen-Cilag: 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. Cibeira:Janssen-Cilag: 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. Blade:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Allogeneic Hematopoietic Stem Cell Transplant in Advanced Multiple Myeloma: Experience from a Single Center

Blood ◽

10.1182/blood.v126.23.5536.5536 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5536-5536

Author(s):

Yizel Elena Paz Nuñez ◽

Beatriz Aguado Bueno ◽

Isabel vicuña Andrés ◽

Ángela Figuera Álvarez ◽

Miriam González-Pardo ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Hematopoietic Stem

Abstract Introduction The prognosis of patients with multiple myeloma (MM) has improved in the last years due to the important advances in the knowledge of the biology of the disease, the implementation of new drugs and the incorporation of autologous hematopoietic stem cell transplant (autoHSCT). The allogenic hematopoietic stem cell transplant (alloHSCT) continues to be controversial: it offers a curative potential but with the cost of high toxicity, limiting the procedure to those young patients with a high-risk disease. This procedure shall be performed in expert centers and, whenever possible, in the context of a clinical trial. In the following we describe the experience of our center with alloHSCT in advance multiple myeloma patients. Patients and methods A total of 18 patients were diagnosed with multiple myeloma received an alloHSCT during a 13 year period (1996-2013), with a median age of 46 ± 5.9 years. All of our patients received an allogenic HLA matched sibling donor with reduced-intensity conditioning. The majority of patients were transplanted because of advanced disease, relapse after an autologous transplant or as part of a sequential transplant in patient with a high risk disease. One patient received, in two occasions, an alloHSCT. Around 70% of patients had received more than 3 previous lines of treatment including, in nearly 95%, an autoHSCT. Patient's characteristics can be found on table 1, characteristics of the procedure can be found in table 2.Table 1.Patient«s CharacteristicsN (%)GenderMale Female10 (55,5%) 9 (44,4%)Secreted ProteinIgGκ IgG λ IgA κ BJ Plasmocitoma8 (44,4%) 4 (22,2%) 2 (11,1%) 3 (16,7%) 1 (5,6%)Debut DS stageII-A II-B III-A III-B Plasmocitoma5 (27,8%) 1 (5,6%) 8 (44,4%) 3 (16,7%) 1 (5,6%)Cytogentics at diagnosisMissing Unfavorable Favorable10 (55,5%) 6 (33,3%) 2 (11,1%)Previous lines of treatment²2 3-4 ³56 (33,3%) 10 (55,5%) 2 (11,1%)Previous autoHSCTYes No17 (94,5%) 1 (5,6%)Previous radiotherapyYes No8 (44,4%) 10 (55,6%)Disease status at transplantComplete remission Partial remission Relapse9 (50,0%) 3 (16,7%) 6 (33,3%)Table 2.Treatment characteristicsN (%)Conditioning regimenMyeloablative Reduced-intensity6 (33,3%) 12 (66.7%)Stem cell sourceBone marrow Peripheral blood4 (22.2%) 14 (77.8%)GVHD prophylaxisCsA+MTXCsA+CSCsA+MMF10 (55.6%) 3 (16.7%) 5 (27.8%)InfectionsYes No16 (88.9%) 2 (11.1%)MucositisYes No12 (66.7%) 6 (33.3%)Acute GVHDYes II-IV III-IV No4 (22.3%) 3 (16.7%) 1 (5.6%) 14 (77.8%)Chronic GVHDNo Limited Extensive8 (44.3%) 5 (27.8%) 5 (27.8%) Results: Transplant related mortality (TRM) before day 100th was one case due to a thromboembolic event. Global TRM was 16.6% (3 cases). The incidence of acute graft versus host disease (aGVHD) was 22%, controlled on most cases when corticosteroids were initiated. More than half of the patients developed chronic graft versus host disease (cGVHD), with an equal distribution on either presentation as limited or extensive. (Table 2) The total number of patients eligible for analysis was 17 (one patient was lost on follow-up). With a median follow up of 11 years, the overall survival (OS) was of 8.06 years [IC 95% 4,33-11,78] (figure 1.) and the estimated progression free survival (PFS) was of 25.83 months [IC 95% 8.87-42.79](figure 2). A total of 5 (29,4%) patients are still alive and 2 (11,7%) of them are in complete remission, of these 1 patient did not have a previous autoHSCT with a follow up of almost 15 years. Conclusions: Our results are similar to those reflected on the literature1-2. However we have to point out that our population is homogenous with advanced MM with more than 3 previous lines of treatment including in most cases auto-HSCT. In spite of this, morbility and mortality in our cohort was acceptable with the limitation of a high rate of cGVHD. There is a need of more studies including more patients to evaluate the role of alloHSCT in the era of new drugs for MM. References 1. Rosi-ol L et al. Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution. Bone Marrow Transplant. 2015. 2. Beaussant Y et al. Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Retrospective Study of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Biol Blood Marrow Transplant. 2015 Disclosures Alegre: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: 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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