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

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

Timing of Daratumumab Administered Pre-Mobilization in Multiple Myeloma Impacts Pre-Harvest Peripheral Blood CD34+ Cell Counts and Plerixafor Use

Blood ◽

10.1182/blood-2020-140811 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Danny Luan ◽

Paul J Christos ◽

Michael Ancharski ◽

Danielle Guarneri ◽

Roger Pearse ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Stem Cell Mobilization ◽

Newly Diagnosed ◽

Advisory Committees ◽

Peripheral Blood Cd34 ◽

Hematopoietic Recovery ◽

Cell Mobilization

Background: Daratumumab (DARA) is a monoclonal antibody which targets CD38 on plasma cells and B cell progenitors. DARA has been effectively combined with other therapies in newly diagnosed and relapsed/refractory multiple myeloma (RRMM), while DARA-based induction regimens in transplant-eligible patients (pts) are increasingly being used in clinical practice. Given that hematopoietic stem cells also express CD38, DARA may potentially affect stem cell mobilization and hematopoietic reconstitution following autologous stem cell transplant (ASCT). Although no clinically significant impact of DARA on stem cell mobilization or hematopoietic recovery was described in large phase 3 trials of triplet induction regimens +/- DARA in newly diagnosed MM, stem cell yields were lower and plerixafor more commonly used in the DARA-containing arms [Moreau et al, Lancet 2019; Voorhees et al, Blood 2020]. Significantly longer time to neutrophil (PMN) engraftment was also reported in pts receiving DARA-based induction who underwent upfront ASCT [Al Saleh et al, Am J Hematol 2020]. In this study, we examine the impact of timing of DARA administration pre-mobilization on day 4 pre-harvest peripheral blood CD34 cell count, stem cell apheresis yield, and post-ASCT engraftment. Methods: Between 1/1/2016 and 12/31/2019, newly diagnosed and RRMM pts receiving DARA-based induction regimens with ≥1 dose of DARA administered within 1 month prior to stem cell mobilization were identified retrospectively and compared to matched controls receiving similar induction regimens without DARA. Granulocyte colony-stimulating factor (G-CSF) was administered per institutional standards and plerixafor added based on day 4 pre-harvest peripheral blood CD34 counts. PMN and platelet engraftment post-ASCT was defined as the first of 3 consecutive days with sustained PMN count >500 x 106/L and independence from platelet transfusion in the preceding 7 days with a count >20 x 109/L, respectively. Pre-harvest peripheral blood CD34 counts and stem cell apheresis yields were obtained from the Cellular Therapy Laboratory at NewYork-Presbyterian Hospital. The study was approved by the Weill Cornell Medicine IRB. Results: We identified 16 pts who received DARA-based induction with ≥1 dose of DARA administered within 1 month of apheresis (DARA group) and 16 non-DARA-containing regimen-matched controls (non-DARA group). Demographics of the DARA and non-DARA groups were well matched (Table 1). DARA pts received their last dose of DARA a mean of 17.3 days prior to the first day of apheresis, with 8 pts receiving their last dose within 2 weeks and the remaining 8 pts between 2 weeks and 1 month prior. Overall, mobilization outcomes were inferior in the DARA group (Table 2). DARA pts had significantly lower day 4 pre-harvest peripheral blood CD34 counts compared to non-DARA pts (17.2 vs 35.4 cells/µL; P=0.0146). Institutional algorithm required plerixafor to be given for day 4 CD34 count ≤40 cells/µL. Fifteen of the 16 DARA pts received plerixafor vs. 11 non-DARA pts (P=0.07). Additionally, DARA pts required significantly more apheresis days (2.4 vs 1.6 days; P=0.0279). Differences in stem cell yield were not significant (8 vs 10 x106cells/kg; P=0.1391). Hematopoietic recovery post-ASCT was not affected by DARA administered in the month preceding mobilization. Conclusions: In summary, we report lower day 4 pre-harvest peripheral blood CD34 count, increased requirement for plerixafor, and longer apheresis duration in newly diagnosed and RRMM pts receiving DARA within 1 month ofstem cell mobilization. These limitations are largely overcome by plerixafor usage which, combined with G-CSF, resulted in successful stem cell collection in all patients. Limitations in our study include small sample sizes, retrospective control selection, and fewer pts in the DARA group achieving ≥VGPR prior to mobilization. Nevertheless, our findings are consistent with inferior mobilization outcomes reported in the DARA-containing arms of phase 3 trials of triplet induction +/- DARA and highlight the nearly universal requirement for plerixafor usage when DARA is administered within a month prior to apheresis. Prospective study of day 4 pre-harvest peripheral blood CD34 counts and other predictors of stem cell yield should be incorporated into future clinical trials of CD38 monoclonal antibody-based induction regimens for transplant-eligible MM pts. Disclosures Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Niesvizky:GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Rosenbaum:Amgen: Research Funding; GlaxoSmithKline: Research Funding; Akcea: Honoraria; Celgene: Honoraria; Janssen: Research Funding.

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

Factors Influencing Long-Term Hematopoietic Function Following Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.2186.2186 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2186-2186

Author(s):

Alissa Visram ◽

Natasha Kekre ◽

Christopher N. Bredeson ◽

Jason Tay ◽

Lothar B. Huebsch ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Infection Rates ◽

Advisory Committees ◽

Cd34 Cells ◽

Significant Difference

Abstract Background/Objective: Mobilized peripheral blood hematopoietic progenitor cells are the most common stem cell source for autologous hematopoietic stem cell transplantation (auto-HSCT). Successful short-term stem cell engraftment requires collection of at least 2x106 CD34+ cells/kg. The American Society of Bone Marrow Transplantation (ASBMT) recommends a stem cell infusion target of 3-5 x106 cells/kg (Giralt et al. 2014). However, the number of CD34+ cells to reinfuse to ensure long-term engraftment has not been established. Plerixafor, a reversible CXCR4 antagonist, increases CD34+ cell yield at collection even in patients who are predicted poor mobilizers (PPM). Although plerixafor could be used universally for all collections, this may not be the most cost-effective strategy (Veltri et al. 2012). This study sought to determine the minimum number of CD34+ cells/kg required for adequate long-term hematopoiesis, identify factors associated with poor long-term hematopoiesis, and determine if plerixafor mobilization improved long-term peripheral blood counts. Methods: A retrospective chart review was conducted on patients who underwent auto-HSCT between January 2004 and September 2013 at The Ottawa Hospital, for management of hematological malignancies. Peripheral blood cell counts were collected from 1 to 5 years after auto-HSCT, or until disease relapse. Poor long-term hematopoiesis was defined as an ANC <1 x109/L, hemoglobin <100 g/L, or platelets <100 x109/L. Patients were stratified into groups based on the infused CD34+ concentration (in cells/kg), and the proportion of patients with poor long-term hematopoiesis at 1, 2, 3, 4, and 5 years post auto-HSCT was compared with chi square tests. Long-term clinical outcomes (platelet and packed red blood cell transfusions, and post auto-HSCT infection rates) were compared between plerixafor-mobilized patients and PPM (defined as patients with pre-collection CD34+ <2 x 106 cells/kg) with standard mobilization regimens. Results: This study included 560 patients who underwent auto-HSCT, 210 with multiple myeloma and 350 with lymphoma. At 1 and 5 years post auto-HSCT 377 and 104 patients were included, respectively. A dose dependent improvement 1 year after auto-HSCT was seen in patients who received 0-2.99 x 106 CD34+ cells/kg (24.4%, n= 41) compared to patients who received 5-9.99 x 106 CD34+ cells/kg (11%, n=154, p=0.051) and ³10 x 106 CD34+ cells/kg (4.5%, n=66, p=0.006). Though there was a trend towards lower CD34+ infusions and poorer hematopoietic function (see table 1), there was no statistically significant difference in hematopoietic function based on CD34+ infusion concentrations after 1 year post auto-HSCT. 10 patients received <2 x106 CD34+ cells/kg, of whom the rate of inadequate hematopoiesis was 33% at 1 year (n=6) and 0% (n=1) at 5 years post auto-HSCT. Factors that increased the risk of poor hematopoiesis over the course of study follow up, based on a univariate analysis, included advanced age (OR 1.189, p=0.05), multiple prior collections (OR 2.978, p=0.035), and prior treatment with more than two chemotherapy lines (OR 2.571, p=0.02). Plerixafor-mobilized patients (n=25), compared to PPM (n=197), had a significantly higher median CD34+ cell collection (4.048 x109/L and 2.996 x109/L cells/kg, respectively, p=0.005). There was no significant difference in overall cytopenias, transfusion requirements, or infection rates between plerixafor-mobilized and PPM patients over the course of the study follow up. Conclusion: Low pre-collection CD34+ counts, advanced age, multiple prior collections, and more than two prior chemotherapy treatments adversely affected long-term hematopoiesis post auto-HSCT. We support the transfusion target of 3-5 x 106 cells/kg, as proposed by the ASBMT, given that at 5 years post auto-HSCT there was no statistical or clinically significant difference in hematopoietic function with higher CD34+ infusion targets. While mobilization with plerixafor significantly increased overall CD34+ cell collection when compared with PPM, long-term hematopoietic function and clinical outcomes were not different. This finding supports the practise of limiting plerixafor use only to patients who are PPM, thereby facilitating adequate stem cell collection and early engraftment, as opposed to universal plerixafor mobilization. Disclosures Sabloff: Lundbeck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Alexion: Honoraria.

Download Full-text

Peripheral Blood Stem Cell Collection In Patients Undergoing Induction Therapy with Lenalidomide Based Regimens: Failure Rates and Salvage Approaches

Blood ◽

10.1182/blood.v116.21.2253.2253 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2253-2253

Author(s):

Shirshendu Sinha ◽

Morie Gertz ◽

Martha Lacy ◽

Angela Dispenzieri ◽

Suzanne Hayman ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Colony Stimulating Factor ◽

Advisory Committees ◽

Cd34 Cells ◽

Cell Mobilization ◽

Stimulating Factor ◽

Stem Cell Collection

Abstract Abstract 2253 Background: Lenalidomide based combinations are among the most common initial therapies for myeloma. Previous studies have suggested that lenalidomide therapy can result in suboptimal stem cell collection in patients eligible to undergo autologous stem cell transplantation, especially older patients after prolonged exposure to the drug. Many salvage approaches are used when attempting repeat stem cell collection in this patient group. Patients and Methods: Two hundred twenty four patients who underwent stem cell collection following lenalidomide-dexamethasone induction from July 2004 and December 2009 were included in the current analysis. Data pertaining to the duration of lenalidomide therapy, stem cell mobilization regimen, and the collection yields were collected from the medical records. Results: The median age at mobilization was 60.6 years (range; 29, 76) and 136 (60%) were male. There were a total of 245 collection attempts from among 224 patients, 21 (9.8%) patients attempting to remobilize after failing to collect the desired numbers of stem cells at the first attempt. We first analyzed the results of the initial collection attempt. The median duration of lenalidomide therapy prior to stem cell collection was 4 months (range; 1, 26). The mobilization strategies were GCSF (Granulocyte Colony Stimulating Factor) alone in 151 (67%) patients, cyclophosphamide (CTX) followed by GCSF in 29 (13%) patients, and GCSF plus AMD3100 in 44 (20%) patients. Among those receiving AMD3100, it was added either due to peripheral blood CD34 cell count not reaching the threshold for initiation of harvest or for poor first day CD34 cells collection in 34 patients and given in a planned fashion in 10 patients. Overall 15 patients (7%) failed to reach the peripheral CD34 cell counts required to initiate apheresis, and among those starting apheresis 6 patients failed to collect at least 2 million CD34 cells/kg; a cumulative failure rate of 9%. Another 18 (8%) patients failed to collect at least 4 million CD34 cells /kg. The CD34 cells yield on day 1, the total yield, number of collections, the average daily yield and the percentage of the targeted cells collected for each mobilization strategy including failure rates are detailed in the table. Twenty-one patients reattempted stem cell mobilization; including 14 that failed a first attempt and 7 did who not achieve the intended goal even though they collected more than 2 million CD34 cells/kg. The mobilization regimens were GCSF alone, CTX + GCSF, GCSF + GM-CSF (Granulocyte Macrophage Colony Stimulating Factor) and GCSF + AMD in 5, 8, 3, and 4 patients respectively. All patients collected at least 2 million CD34 cells /kg and 14 patients (70%) collected more than 4 million CD34 cells /kg. The median CD34 cells collected with the second attempt was 5.4 million/kg (rang; 2, 19.5) bringing the median total collection for these 21 patients to 9.6 million/kg (2.6-19.6). Overall, of the 224 patients studied, all but the 6 patients who failed initially and did not attempt a second collection collected at least 2 million CD34 cells /kg and 197 (88%) collected at least 4 million CD34 cells/kg. Conclusion: While the overall failure rate of stem cell collection in patients receiving initial therapy with lenalidomide is 10%, a risk adapted approach of adding AMD3100 appear to decrease the risk of failure. However, majority of patients failing a stem cell harvest attempt can be salvaged with a second collection allowing these patients to proceed to a stem cell transplant if desired. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding. Lacy: Celgene: Research Funding. Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Micallef: Genzyme: Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Download Full-text

Temporal Changes in Plerixafor Administration Do Not Impact Hematopoietic Stem Cell Mobilization Efficacy: Results of a Prospective Clinical Trial

Blood ◽

10.1182/blood.v118.21.2988.2988 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2988-2988

Author(s):

R. Donald Harvey ◽

Sagar Lonial ◽

Heather Renfroe ◽

Rajni Sinha ◽

Christopher R Flowers ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Peripheral Blood ◽

Research Funding ◽

Published Data ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Dosing Interval ◽

Cell Counts ◽

Cd34 Cells

Abstract Abstract 2988 Objectives: Plerixafor (AMD3100, Mozobil) with filgrastim (G-CSF, Neupogen) is approved for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and multiple myeloma (MM). Plerixafor pharmacokinetics (PK) and pharmacodynamics (PD) are well described, with linear, dose-dependent PK following subcutaneous (SC) administration, peak concentrations 30–60 mins post-injection and an elimination half-life (t1/2) of 5.3 hr. In pharmacodynamic studies of plerixafor in conjunction with filgrastim in healthy volunteers, peak CD34+ cell counts occur 10–14 hours following administration, however, data is limited in the 14–24 hr timeframe. Plerixafor labeling requires SC dosing approximately 11 hours prior to apheresis, which translates into dosing 10 :00 PM the night before apheresis, and 54% of MM patients collect ≥ 6 × 106 CD34+ cells/kg following a single apheresis procedure. The current regimen is inconvenient for patients and requires additional health care resources. Based on PK and PD, we hypothesized that plerixafor given at 3 :00 PM (17 hr prior to apheresis) would yield equivalent CD34+ HSC yield to 10 :00 PM dosing in MM patients. Methods: In a Simon's two-stage design, we enrolled MM patients undergoing cytokine-only HSC mobilization. All subjects received filgrastim 7.5 mcg/kg SC BID for 4 days followed by plerixafor (0.24 mg/kg SC daily) for up to 4 days beginning at 3 :00 PM the day prior to the first day of a 24-liter apheresis procedure at 8 :00 AM. Target CD34+ HSC collection for stem cell transplant (SCT) was ≥ 10 × 106 CD34+ cells/kg. Blood samples for CD34+ fluorescence-activated cell sorting analysis were collected prior to the first plerixafor dose and at 1, 3, and 17 ± 1 hr, then daily prior to apheresis as needed. Results: Thirty patients (17 female, median age 59 years [range 44–70]) were evaluable; 27 received 1 pre-mobilization regimen (RVD n=20, VTD n=2, VD n=2, V/PLD/D n=1, VT n=1, RD n=1) for a median of 4 (1–6) cycles. Three received 2 regimens [CMF × 6 (breast cancer), then VTD × 5; RD × 4, then RVD × 4; and V/PLD × 1 with maintenance R]. Six patients received prior radiation. Mean (± SD) CD34+ cell counts in peripheral blood pre-plerixafor and 1, 3, and 17 hr post-first dose increased through the dosing interval (Figure). Twenty-two (73%) patients collected target cell numbers in 1 day of apheresis, 7 (23%) in 2 days, and 1 (3%) in 3 days. Twenty-seven (90%) patients collected ≥ 6 × 106 CD34+ cells/kg in 1 day. Institutional data with filgrastim 7.5 mcg/kg SC BID for 4 days alone in MM in 22 subjects showed a day 1 collection of ≥ 10 × 106 CD34+ cells/kg in 18% of patients (Renfroe H, et al. Transfusion Feb 2011). Adverse events were generally mild and consistent with known side effects of the combination [gastrointestinal disorders (diarrhea, nausea) and injection site reactions]. To date, 16 (53%) patients have proceeded to autologous SCT with melphalan conditioning and all patients have engrafted, with median time to an ANC ≥ 500/mm3 of 13 (range 11–15) days and platelets ≥ 20, 000/mm3 of 16 (range 11–21) days. Conclusion: This is the first prospective trial demonstrating the safety and efficacy of plerixafor given 17 hr prior to apheresis. Pharmacodynamic data showed the peripheral blood CD34+ cell population increased throughout the dosing interval, with a 4.6-fold increase over pre-plerixafor counts at 17 hr. Comparison with historical institutional controls and published data suggests this regimen yields at least equivalent, if not superior, collection rates with one apheresis procedure. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: 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

Successful Mobilization of Peripheral Blood Stem Cells After Intensive Bendamustine Pre-Treatment In Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.4439.4439 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4439-4439

Author(s):

Wolfram Pönisch ◽

Julia Wiesler ◽

Sabine Leiblein ◽

Elvira Edel ◽

Haifa K. Al-Ali ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Median Number ◽

Advisory Committees ◽

Peripheral Blood Cd34 ◽

Ortho Biotech ◽

Cell Mobilization

Abstract Abstract 4439 Introduction The alkylating agent bendamustine has structural similarities to both alkylating agents and purine analogs, and is effective in the treatment of patients with multiple myeloma. So far, no data are available on stem cell toxicity or on stem cell mobilization. Since autologous stem cell transplantation is an established treatment for multiple myeloma after primary treatment, we were interested in analysing the experience of stem cell mobilization after bendamustine treatment. Material and Methods A retrospective analysis over a period of fifteen years was carried out in 56 (34 male and 22 female) patients with multiple myeloma after bendamustine pretreatment at the university hospitals Leipzig and Heidelberg. Patients had a median age of 58 (range 31–72) years. The median number of cycles was 3 (range 1–10) and the cumulative bendamustine dose ranged from 120 to 2400 mg/qm. The mobilization regimen in 37 cases was either cyclophosphamide 4 g/qm (n=33) or 7 g/qm (n=4) followed by G-CSF (2×5 ug/kg s.c.). Alternative regimens such as CAD, CED, TCED and others were used for mobilization in the remaining 19 patients. Apheresis was started as soon as peripheral blood CD34+ counts exceeded 10×106/l with a harvest target of 4×106 CD34+/kg using 4 times the blood volume. The minimal accepted target was 2×106 CD34+/kg. Results Stem cell harvest was successful in 54 of the 56 patients. In one patient the peripheral blood CD34+ cell count failed to reach 10 × 106/l and no apheresis was performed. In one further patient a rapid decrease in peripheral blood CD34+ counts resulted in insufficient recovery of stem cells in the apheresis product. In 18 out of 54 patients (33%) the target was reached with a single apharesis. The median number of aphareses in the 54 patients was 2 (range 1–7) and the median CD34+ cell-count obtained was 5.5 (range 1.7–20.4) × 106/kg. Engraftment was successful in 52/53 patients receiving a stem cell transplant. One patient was successfully harvested and did not receive the transplant yet. Conclusion From this retrospective analysis we conclude that mobilization of PBSC is possible after intensive bendamustine pretreatment. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Research Funding; Celgene: Research Funding; Chugai Pharma: Research Funding; Amgen: Research Funding.

Download Full-text

Plerixafor (Mozobi ®)Plus G-CSF Is More Effective Than Placebo Plus G-CSF in Mobilizing CD34+ Hematopoietic Stem Cells in Patients with Multiple Myeloma Who Have Low (<20 cells/μl) Peripheral Blood CD34+ Cell Count.

Blood ◽

10.1182/blood.v114.22.3230.3230 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3230-3230 ◽

Cited By ~ 1

Author(s):

Auayporn P. Nademanee ◽

Edward Stadtmauer ◽

Ivana N Micallef ◽

Patrick Stiff ◽

Sachin Marulkar ◽

...

Keyword(s):

Placebo Group ◽

Cell Count ◽

Board Of Directors ◽

Research Funding ◽

Fold Increase ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cell Counts ◽

Cd34 Cells ◽

Equity Ownership

Abstract Abstract 3230 Poster Board III-167 Background Pre-apheresis peripheral blood (PB) CD34+ cells of < 20 cells/μl is a significant risk factor for poor hematopoietic stem cell (HSC) mobilization and collection in patients with multiple myeloma (MM) undergoing autologous HSC transplantation (auto-HSCT). PB CD34+ cells are routinely monitored to optimize the timing and success of HSC collection after mobilization with cytokines ± chemotherapy. This analysis was designed to compare the efficacy of plerixafor + G-CSF to placebo + G-CSF for mobilization in patients with MM who had pre-apheresis PB CD34+ cell counts < 20 cells/μl. We hypothesized that the addition of plerixafor to G-CSF would improve the stem cell yield in these patients with baseline CD34+ cells < 20 cells/μl. Methods Data were obtained from a prospective, randomized, double-blind, placebo-controlled, phase 3 clinical trial that compared the safety and efficacy of plerixafor (0.24 mg/kg/day SC) + G-CSF (10 μg/kg/day) to placebo + G-CSF for mobilization and auto-HSCT in patients with MM. PB CD34+ cell count was measured on Day 4, prior to first plerixafor/placebo dose, and on Day 5, 10-11 hours post study treatment. The proportion of patients achieving the minimal (≥2 × 106 CD34+ cells/kg) or optimal (≥6 × 106 CD34+ cells/kg) cell doses in 2 apheresis days, apheresis yields, and time to engraftment were compared between the plerixafor and placebo groups for PB CD34+ cell count <10 cells/μl (PB<10) and <20 cells/μl (PB<20). Results In the plerixafor group (n=148), 27 (18%) and 56 (38%) patients had Day 4 PB CD34+ cells/μl <10 and <20 which was as expected identical to the 30 (19%) and 60 (39%) patients in the placebo group, respectively (n=154). Patient characteristics were similar in both groups. Plerixafor + G-CSF resulted in a statistically significant increase in the absolute PB CD34+ cells/ml on Day 5 compared to placebo + G-CSF (p<0.001; Table 1). For patients with PB <10, the median fold increase in PB CD34+ cells in the plerixafor (n = 27) vs. placebo (n = 30) groups was 9.6 vs. 2 (p<0.001). Similarly, for patients with PB <20 the median fold increase in PB CD34+ cells in the plerixafor (n = 56) vs. placebo (n = 60) groups was 6.6 vs. 2 (p<0.001).The median CD34+ cell yield after 2 aphereses was significantly higher in the plerixafor vs. placebo group: 5.44 vs.1.68 × 106 cells/kg (p<0.001; PB<10) and 7.06 vs. 3.27 × 106 cells/kg (p<0.001; PB <20). The proportion of patients achieving ≥2 × 106 CD34+ cells/kg in 2 aphereses was significantly higher in the plerixafor group compared to the placebo group: 92.6% vs. 43.3 % in patients with PB<10 (p<0.001), and 94.6% vs. 66.7% in patients with PB<20 (p<0.001). Similarly, the proportion of patients achieving ≥6 × 106 CD34+ cells/kg in 2 apheresis days was significantly higher in the plerixafor vs. placebo group: 40.7% vs. 3.3 % in patients with PB<10 (p<0.001), and 55.4% vs. 15% in patients with PB<20 (p<0.001). The median time to platelet (19-20 days) and neutrophil (11 days) engraftment was similar in both groups. Conclusions These data demonstrate that in patients with MM who are predicted to fail mobilization based on low PB CD34+ cell count, the addition of plerixafor to G-CSF allows for 2-day collection of the minimal and optimal cell dose in a greater proportion of patients compared to G-CSF alone. Thus, addition of plerixafor to G-CSF can decrease the risk of poor mobilization in patients with MM who have PB CD34+ cell counts < 20 or even < 10 cells/μl. Disclosures Nademanee: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stadtmauer:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Micallef:Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stiff:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Calandra:Genzyme Corporation: Consultancy, Equity Ownership. DiPersio:Genzyme: Honoraria.

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

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

Blood ◽

10.1182/blood-2019-131594 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2028-2028

Author(s):

Madeline Skousen ◽

Sarah A. Holstein ◽

Matthew A. Lunning ◽

Elizabeth R. Lyden ◽

Gilmore Sheree ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Single Institution ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Neutrophil Engraftment

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