Cell Collection Yield Research Articles

Stem Cell Utilization in the Era of Novel Therapies for Multiple Myeloma

Introduction: Stem cell collection is recommended for patients with newly diagnosed multiple myeloma (NDMM) deemed eligible for autologous stem cell transplantation (ASCT). Standard practice at most institutions is to collect an adequate number of stem cells for at least 2 ASCTs, but the benefit of maintaining extra stem cells in storage for future use beyond an initial ASCT warrants re-evaluation in the current era of novel therapies and evolving MM clinical practice. To address this, we reviewed the utilization rates and indications for the use of stored stem cells (SSC) at our institution. Methods: We conducted a single-center, retrospective study of 1470 patients with NDMM who collected sufficient stem cells for at least 2 ASCTs and underwent at least one ASCT at Memorial Sloan Kettering Cancer Center between January 2007 and December 2022. From this cohort, we assessed rates of stem cell utilization for second, non-tandem (salvage) ASCT and/or stem cell boost over time and determined progression-free survival (PFS) and overall survival (OS) from the time of salvage ASCT using the Cox proportional hazard model. Results: The median patient age atinitial ASCT was 61 years (range 24-81), with 58% male, 25% International Staging System stage III, and 42% (542/1283) with at least one high-risk cytogenetic alteration. Granulocyte-colony stimulating factor, either with or without plerixafor, was used for stem cell mobilization in 70% (834/1193) of patients, with the remaining patients undergoing chemotherapy-based mobilization, including high-dose cyclophosphamide (15%) or other multiagent chemotherapy regimens (15%). The median total CD34 + cell collection yield was 10.3 × 10 6/kg (interquartile range, IQR, 8-13). During the entire study period, SSC were used for 14.6% (214/1470) of patients, with 11.2% (n=165) for a salvage ASCT and 2.1% (n=31) for a stem cell boost. Seven patients received both a salvage ASCT and a boost. An additional 25 patients had upfront tandem ASCT (none since 2015) and were excluded from this analysis. Notably, from 2019 to 2022, the annual utilization of salvage ASCT increased compared to pre-2019 levels (median=21, range 11-27 vs. pre-2019 median=7, range 4-12), as did stem cell boosts (median=4, range 1-6 vs. pre-2019 median=1, range 0-3), despite a decline in numbers during the COVID-19 pandemic (Figure 1). The median age at SSC use was 61 years (range 29-78). The median number of prior lines of therapy (LOT) before the use of SSC was 4 (IQR: 2-7) for salvage ASCT and 6 (IQR: 1-6.5) for boosts. The median infused stem cell dose (CD34+ cells/kg) was 4.4 × 10 6 (range 3.2-5.7) for salvage ASCT and 3.1 × 10 6 (range 2.2-3.6) for boosts. The median PFS after salvage ASCT was 16 months (95% confidence interval, CI, 12-21), and the median OS was 37 months (95% CI 29 - 53). On multivariable analyses, receipt of fewer lines of therapy was the sole favorable prognostic factor for PFS and OS. Among patients with ≤ 3 prior LOT, the median PFS after salvage ASCT was 32 months (95% CI 22-42), while those with > 3 LOT had a median PFS of 8.0 months (95% CI 5.8-12) (Figure 2). Post-treatment therapy after salvage ASCT or stem cell boost most commonly included various MM triplet regimens, chimeric antigen receptor T-cell therapy, and bispecific T-cell engagers. Conclusion: While overall rates of SSC utilization at our institution remain low, rates have increased in recent years, as both salvage ASCT and stem cell boosts provide effective platforms for treating disease and treatment-related refractory cytopenias as a bridge to next therapy for patients with advanced MM. Ultimately, institutional practices for stem cell collection and storage require optimizing the balance of clinical utility with resource allocation and costs of maintaining SSC.

Prior Daratumumab Exposure and It's Correlation to Parameters Related to Apheresis Prior to Hematopoietic Stem Cell Transplantation in Multiple Myeloma

A number of recent studies have brought to light the potential detrimental effect the biologic monoclonal antibody daratumumab, directed towards CD38, may have on the collection of stem cell collection for hematopoietic stem cell transplantation (HSCT). In our evaluation of this claim, we retrospectively reviewed multiple myeloma patients who underwent autologous HSCT at a major tertiary transplant center between 2017 and 2022. A total of 240 patients were identified which included 62 patients who received daratumumab prior to stem cell collection and 178 patients who had no prior daratumumab exposure. Basic demographic data was collected as well as radiation, chemotherapy, and smoking history. No significant differences were identified between the groups based on demographics, smoking, or radiation exposure. Parameters related to peripheral stem cell collection were identified and recorded. We found that in patients exposed to daratumumab prior to apheresis, the mean number of days of apheresis required to reach the target collection goal was statistically increased compared to control (1.42 days ± 0.07 vs 1.26 ± 0.03; p<0.05). Furthermore, medications used to increase peripheral stem cell collection yield were also increased. It was demonstrated that the mean number of doses of plerixafor and G-CSF analogs were increased in the daratumumab group vs the control (1.08 ± 0.12 vs 0.6 ± 0.05; p<0.001 and 5.98 ± 0.31 vs 5.17 ± 0.06; p <0.001 respectively). Total number of stem cells collected both as an absolute number and controlled for the number of days of apheresis were lower in the daratumumab group compared to the control (5.31x10^6 ± 0.31 vs 6.68x10^6 ± 0.20; p<0.05 and 4.16x10^6 ± 0.32 vs 5.84x10^6 ± 0.21; p < 0.001 respectively). These results suggest that pre-apheresis exposure to daratumumab has a detrimental effect on peripheral stem cell collection. These results have a significant implications for both long term patient care and healthcare system resource utilization. The clinical outcome implications of daratumumab are currently not well known and further study is needed to determine if alterations in stem cell collection protocols would result in improved stem cell collection yields for patients with pre-collection daratumumab exposure. All data is expressed as mean ± SEM

Despite Use of Upfront Plerixafor and G-CSF, Daratumumab Exposure Reduces Stem Cell Mobilization in Patients with Multiple Myeloma

Introduction Daratumumab is an anti-CD38 IgG1k monoclonal antibody with direct tumor killing and immunomodulatory mechanisms of action which was shown to have clinical benefits when added to the standard-of-care induction regimen in transplant eligible multiple myeloma (MM) patients. However, prior studies have indicated a potential reduction in stem cell yield in patients exposed to daratumumab prior to stem cell mobilization. Additionally, prior studies have not utilized combination mobilization regimens with G-CSF and the CXCR4 antagonist plerixafor as standard-of-care, which may overcome the deleterious effect of daratumumab. In this study, we investigated the stem cell yield of plerixafor-treated patients with daratumumab exposure compared to those without. Methods We conducted a retrospective study of patients with MM at our institution who underwent autologous stem cell mobilization and collection during first-line treatment over a 15-month period from 2021-2022. Following induction, patients underwent mobilization with a regimen of G-CSF for 5 days with plerixafor on the 4th day. Circulating CD34+ stem cells were enumerated on the 5th day, after which patients underwent approximately 20L apheresis with a collection goal of 5x106 CD34+ cells/kg of body weight. The primary endpoint of this study was the comparison of circulating CD34+ cells between patients who received daratumumab during induction and those who did not. Secondary endpoints included collection CD34+ yield and proportion who met the collection goal. Results 123 patients were included in the analysis. The median age was 65 (range: 34-77), 54% were male, and 84% were White. Twenty-two percent were stage I, 58% stage II, and 19% stage III by the Revised International Staging System. Forty-seven percent received daratumumab during induction. Of those, the median number of cycles administered was 4 (range: 1-5). Ninety percent received daratumumab in combination with bortezomib, lenalidomide and dexamethasone. The two cohorts were balanced in terms of age, gender, race, and exposure to lenalidomide, alkylators and radiation during induction. Patients with daratumumab exposure had a mean mobilization of 57.5 CD34+ cells/mcl compared to 96.4 for those without (p < 0.001). The mean CD34+ cell collection yield in 1 apheresis procedure was 6.0 x 106 cells/kg compared to 10.6 x 106 cells/kg (p < 0.001). Fifty-three percent of patients with daratumumab exposure met the collection goal compared to 80% of patients without (p < 0.001). Of the patients who did not meet the goal in one apheresis procedure, the majority were able to meet the goal with 1-3 additional days of apheresis (Figure 1). However, only 86% of patients with daratumumab exposure met the collection goal compared to 97% of those without (p < 0.001). Ten patients failed to collect 2.0 x 106 cells/kg, the institutional minimum for transplantation, 9 of which received daratumumab during induction. Eight were able to collect the minimum with an additional 1-3 days of apheresis; 2 patients required an additional mobilization procedure and collection but were able to proceed to transplantation. After adjusting for covariates including age, gender, race, weight, and exposure to lenalidomide, alkylators, and radiation, daratumumab exposure was associated with a 37.9 cells/mcl decrease in mean mobilization of CD34+ and 4.2 x 106 cells/kg decrease in CD34+ cell collection (both p < 0.001). Alkylator exposure was associated with a 43.3 cells/mcl decrease in mean mobilization of CD34+ (p = 0.040) and 4.1 x 106 cells/kg decrease in CD34+ cell collection (p = 0.057). Lenalidomide exposure was associated with a 103.4 cells/mcl decrease in mean mobilization of CD34+ (p <0.001) and 8.7 x 106 cells/kg decrease in CD34+ cell collection (p <0.001). Conclusion Inclusion of daratumumab in the induction regimen for transplant-eligible patients with MM resulted in a significant reduction in stem cell mobilization and stem cell yield, even with the use of plerixafor-containing mobilization regimens. This reduction was similar to alkylator exposure but less than lenalidomide exposure. With the increasing use of quadruplet induction regimens, the frequency of mobilization failure is likely to increase in the future and new mobilization regimens and approaches are needed to guarantee adequate cell yields without the need for additional days of apheresis and/or mobilizations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A comparison of four leukapheresis methods to harvest an optimal dose of CD34+ cells: A single center experience

Chemokine receptor CXCR4 antagonist plerixafor (Px) as well as high volume (HV) leukapheresis have been shown to reduce hematopoietic stem progenitor cell (HSPC) mobilization failure rates. However, no direct comparisons of such methods currently exists. We compared the HSPC collection yield based on basal peripheral blood CD34+ cell numbers in patients diagnosed with multiple myeloma or non-Hodgkin's lymphoma undergoing autologous stem cell transplantation in a retrospective chart review. The leukapheresis methods used included HV versus regular volume (RV) with or without Px. There were 116 patients in the study group while the historical control group had 34 patients. Control group underwent RV leukapheresis without Px. Addition of Px or HV in the study group failed to display significant improvement in CD34+ cell collection yield; however, when basal CD34+ cell numbers were taken into account, both Px + RV and HV without Px increased CD34+ cell collection yield. The collection failure rates of HV without Px group were comparable to Px + RV when the basal CD34+ cell numbers were over 20/μl. Of interest, multivariate linear regression analysis did not detect any significant difference between HV versus Px + RV or other leukapheresis methods in CD34 yields or collection failure rates from a single collection after controlling for other factors (sex, age, or underlying disease). In multivariate analysis, pre apheresis CD34+ cell number was significantly and positively associated with the CD34+ cell yields from a single apheresis. In our studies, the majority of patients can be rescued without Px by HV alone as a potential cost saving approach. In summary, trend in our studies reflects that both Px and HV are capable of reducing the mobilization failure rates except the poorest mobilizers, which will need to be validated in larger studies.

Addition of plerixafor in poorly mobilized allogeneic stem cell donors.

BackgroundPeripheral blood stem cells (PBSCs) are the predominant graft source for adult allogeneic hematopoietic stem cell transplantation (HSCT). In poorly mobilized autologous donors, plerixafor improves collection outcomes. We examine plerixafor use in allogeneic donors who mobilize poorly with granulocyte colony‐stimulating factor (G‐CSF) in those who are healthy and those with pre‐existing medical conditions, and determine the optimal threshold to add plerixafor.Study Design/MethodsWe retrospectively examined all allogeneic PBSC collections from January 2013 to October 2020 at our center. Donors received G‐CSF 10 mcg/kg daily for 4 days before undergoing apheresis collection on day 5. Plerixafor was added based on poor CD34+ cell collection yield after the first or second collection day.ResultsOf the 1008 allogeneic donors, 41 (4.1%) received one dose of plerixafor in addition to G‐CSF due to poor collection yield. After starting plerixafor there was a 0.75‐ to 7.74‐fold (median 2.94) increase in CD34+ yield from the previous day. No donors with G‐CSF‐only mobilization who collected <2.0 × 106 CD34+ cells/kg recipient weight on day one achieved the goal of ≥4.0 × 106 CD34+ cells/kg recipient weight total over 2 days but 59.2% of donors who used rescue plerixafor did.ConclusionDonors both healthy and those with pre‐existing disease responded well to plerixafor with minimal side effects. If the first‐day collection yield is less than ~63% of the collection goal, addition of plerixafor may be necessary to reach the collection goal and limit the number of collection days in allogeneic donors.

Development of a quantitative prediction model for peripheral blood stem cell collection yield in the plerixafor era

Background aimsPredicting autologous peripheral blood stem cell (PBSC) collection yield before leukapheresis is important for optimizing PBSC mobilization and autologous stem cell transplantation (ASCT) for treating hematological malignancies. Although guidelines for plerixafor usage based on peripheral blood CD34+ (PB-CD34+) cell count are available, their predictive performance in the real world remains unclear. MethodsThis study retrospectively analyzed 55 mobilization procedures for patients with non-Hodgkin lymphoma or multiple myeloma and developed a novel quantitative prediction model for CD34+ cell collection yield that incorporated four clinical parameters available the day before leukapheresis; namely, PB-CD34+ cell count the day before apheresis (day −1 PB-CD34+), number of prior chemotherapy regimens, disease status at apheresis and mobilization protocol. ResultsThe effects of PB-CD34+ cell counts on CD34+ cell collection yield varied widely per patient characteristics, and plerixafor usage was recommended in patients with poorly controlled disease or those with a history of heavy pre-treatments even with abundant day −1 PB-CD34+ cell count. This model suggested a more proactive use of plerixafor than that recommended by the guidelines for patients with poor pre-collection condition or those with a higher target number of CD34+ cells. Further, the authors analyzed the clinical outcomes of ASCT and found that plerixafor use for stem cell mobilization did not affect short- or long-term outcomes after ASCT. ConclusionsAlthough external validations are necessary, the results can be beneficial for establishing more effective and safer mobilization strategies.

Local Radiation Therapy Before and During Induction Delays Stem Cell Mobilization and Collection in Multiple Myeloma Patients

In multiple myeloma, local radiation therapy (RT) of osseous lesions before peripheral blood stem cell (PBSC) mobilization is assumed to impair the PBSC mobilization and collection. However, the results of previously published studies are inconsistent and do not evaluate detailed metrics of RT and PBSC outcome parameters. In total, 352 patients undergoing PBSC mobilizations and RT in first-line treatment were evaluated. Patients were grouped into RT (n = 283) and no RT (n = 69) before PBSC mobilization. Except for the International Staging System score, both groups were homogeneous regarding the first diagnosis characteristics, first-line treatments, and response parameters. RT metrics (RT yes versus no, volume of irradiated hematopoietic bone marrow [BM], biologically equivalent doses in 2 Gy fractions [EQD2]) were analyzed for the following PBSC outcome parameters: achievement of the PBSC collection goal, CD34+ cell collection yield, duration of the mobilization phase, and number of leukapheresis (LP) sessions to reach the collection goal. No statistically significant differences in the percentage of collection failures to reach at least 3 sufficient PBSC transplants were identified comparing patients with (n = 32 [11%]) and without RT (n = 4 [6%]) before PBSC mobilization (P = .265). However, patients with RT before PBSC mobilization showed a significant prolongation of the PBSC mobilization (median 1 day, P =.026) and required a higher number of LP sessions to reach the collection goal (median 1 LP, P < .001) compared with patients who received RT after PBSC mobilization. Moreover, patients with RT before PBSC mobilization reached a significantly lower CD34+ cell collection result (mean 8.94 versus 9.81 × 106/kg body weight [bw], P = .002). No correlation was identified between the overall CD34+ cell yield and the volume of irradiated hematopoietic BM or EQD2, respectively. In the RT before PBSC mobilization group, patients who required more than 1 LP session to reach the PBSC collection goal after RT had a significantly higher percentage of radiated hematopoietic BM compared to those who required only 1 LP session (mean 9.7% versus 7.2%, P = .002). Overall, our study indicates a negative impact of RT on PBSC mobilization and collection. Apart from emergency settings, it might be beneficial to postpone RT to a post-PBSC collection time point.© 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Impact of Daratumumab on Stem Cell Collection, Graft Composition and Engraftment Among Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as &amp;lt; 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC &amp;gt;1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count &amp;gt;20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

Low baseline platelet count predicts poor response to plerixafor in patients with multiple myeloma undergoing autologous stem cell mobilization

Background aimsBaseline platelet count has been shown to be a sensitive predictor of autologous peripheral blood progenitor cell collection yield in patients with multiple myeloma mobilized with granulocyte colony-stimulating factor (G-CSF). Patients who mobilize poorly with G-CSF are often treated with plerixafor to enhance mobilization. There are no surrogate markers available to predict response to plerixafor. MethodsWe retrospectively analyzed data from 73 patients with multiple myeloma who did not have adequate mobilization with G-CSF alone and were treated with plerixafor as a rescue agent. ResultsWe found that baseline platelet count directly correlated with peripheral blood CD34+ (PB-CD34+) count after plerixafor treatment (r = 0.36, P < 0.0001) and the number of PB-CD34+ cells collected on the first day of apheresis and inversely correlated with the number of apheresis sessions needed to collect the target number of PB-CD34+ cells (P = 0.0015). Baseline platelet count of 153 000/µL or less was associated with 90% specificity of predicting poor response to plerixafor with a sensitivity of 33%. ConclusionsBaseline platelet count is a good predictor of mobilization response to plerixafor in patients with multiple myeloma.

Single-dose etoposide is an effective and safe protocol for stem cell mobilization in patients with multiple myeloma.

Single-dose etoposide was used an outpatient-based protocol for mobilization in patients with multiple myeloma (MM) for autologous stem cell transplantation (ASCT). Thus, we retrospectively analyzed the efficacy and safety of our one-day protocol in comparison with that of previous methods. We retrospectively analyzed 168 patients with MM who underwent peripheral blood stem cell collection for upfront ASCT between 2008 and 2018. The mobilization protocols included G-CSF alone (G-mobilization), one-day 375 mg/m2 of etoposide (E375), two-days of 375 mg/m2 of etoposide (E750), or one-day high-dose (3.5 g/m2 ) cyclophosphamide (HD CY). For comparison of efficacy of each protocol, collected CD34+ cells over 4 × 106 /kg and under 2 × 106 /kg were defined as "adequate harvest" and "harvest failure," respectively. The median number of collected CD34+ cells was 5.58 × 106 /kg in patients receiving single-dose etoposide, and the percentage of uncomplicated optimal harvest of E375 (65.6%, 21/32) was significantly higher than that of E750 (41.9%, 13/31) and HD CY (31.3%, 15/48). The E375 showed the highest rate of adequate harvest (96.9%, 31/32) compared to that of E750 (87.1%), HD CY (75.0%), and G-mobilization (59.6%). Most E375 patients achieved adequate harvest without complication (29/32, 90.6%), the CD34+ cell collection yield on apheresis days one and two of E375 was not significantly different from that of E750, and no harvest failures occurred for E375. Neutrophil and platelet engraftments were significantly faster in E375 than other groups (P < .001). The use of single-dose etoposide could be an effective and safe method for mobilization in patients with MM.

464 - Influence of Donor Variables on CD34 Stem Cell Collection Yield Comparing Peripheral Blood Progenitor Cell and Bone Marrow Collection at a Single Institution

464 - Influence of Donor Variables on CD34 Stem Cell Collection Yield Comparing Peripheral Blood Progenitor Cell and Bone Marrow Collection at a Single Institution

A Comparison of Cyclophosphamide, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma

▪IntroductionCyclophosphamide, bortezomib, and dexamethasone (CyBor-D) is considered a standard induction regimen for transplant eligible patients with newly diagnosed multiple myeloma (MM) based primarily on phase 2 data. It has not been directly compared to bortezomib and dexamethasone (Bor-Dex) alone. Therefore, we sought to compare the efficacy CyBor-D and Bor-Dex induction in transplant eligible patients treated at a tertiary care center.MethodsA retrospective observational study was performed from a single tertiary care center between January 1, 2008 and April 30, 2016. All transplant eligible patients with MM who received induction chemotherapy with CyBor-D or Bor-Dex and were included. The primary outcome was progression free survival (PFS). Secondary outcomes were response to induction, toxicity, stem cell collection yield and failures, and response to autologous stem cell transplant (autoSCT). Continuous variables were reported as median and compared using Mann-Whitney test. Categorical variables were compared using Pearson's chi-square test. PFS was estimated with Kaplan-Meier.ResultsOne hundred and fifty nine patients were included, 82 (51.6%) treated with CyBor-D and 77 (48.4%) treated with Bor-Dex. The relative proportion of patients treated with CyBor-D increased annually: 1/23 (4%) in 2012, 20/30 (66%) in 2013, 33/34 (97%) in 2014, and 28/28 (100%) in 2015. Patient demographics and disease characteristics were similar between all groups for sex, subtype of MM and stage by the International Staging System. The Bor-Dex group was significantly younger than the CyBor-D group (mean age 56 vs. 61 years, p < 0.001). Median number of cycles was the same for both groups (4, p= 0.73); however, the Bor-Dex group was more likely to have treatment held, reduced or discontinued than the CyBor-D group (19.7% vs. 6.4%, p=0.017). The overall response rate (ORR) was similar between both groups, 88.5% for CyBor-D and 82.7% for Bor-Dex (p=0.36), but patients treated with CyBor-D had deeper responses to induction with 57.5% achieving ≥VGPR whereas 38.7% in the Bor-Dex group achieved ≥ VGPR (p=0.02). The stem cell mobilization regimen was predominantly Cyclophosphamide and GCSF for both groups. Plerixafor use was more common in the CyBor-D cohort, 14.6% vs. 1.3% in Bor-Dex (p=0.002), and there were more collection failures in the CyBor-D group compared to Bor-Dex (6.1% vs. 0%, p=0.03). The median number of CD34 cells collected was higher in the Bor-Dex compared to CyBor-D (9.88 x 106 cells/kg vs. 7.66 x 106cells/kg, p=0.004), however median collection days was similar (1 in both groups, p=0.175). The mobilization toxicity was similar between both groups with a trend towards increased hospitalizations in the CyBor-D group (26% vs. 14%, p=0.075). The conditioning regimen was the same in both groups, predominantly Melphalan 200 mg/m2. Day 100 response was similar, with 76.7% of CyBor-D patients achieving ≥ VGPR vs. 71.21% for Bor-Dex (p= 0.25). The median PFS was 36.5 months in the Bor-Dex group and not yet reached in the CyBor-D group, due to shorter follow up time. However, the percentage of patients free from relapse was similar at 1 year (92.8% for CyBorD vs 98.7% for Bor-Dex) and at 2 years (69.4% for CyBor-D vs 72.9% for Bor-Dex).ConclusionsCyBor-D and Bor-Dex appear to have similar overall efficacy for newly diagnosed transplant eligible patients with multiple myeloma in our cohort. CyBor-D was associated with deeper response to induction, but after autoSCT there was no difference in the depth of response between the two cohorts. Longer follow up is required to detect if the deeper response to induction with CyBor-D leads to differences in PFS. When used with Cyclophosphamide-GCSF mobilization, CyBor-D appears to result in more collection failures and a trend towards increased hospitalizations. Further prospective studies are required to examine this relationship. DisclosuresKew:Celgene: Honoraria. McCurdy:Celgene: Honoraria.

Efficient Stem Cell Collection after Modified Cisplatin-Based Mobilization Chemotherapy in Patients with Diffuse Large B Cell Lymphoma

In patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) is a commonly used regimen for salvage therapy and for mobilization of peripheral blood stem cells (PBSCs). At our center, a modified R-DHAP regimen with administration of 25 mg/m2 cisplatin as a 3-hour infusion over 4 consecutive days, instead of a single infusion of 100 mg/m2 over 24 hours, has been established. The aim of this study was to analyze the efficiency of this modified R-DHAP regimen plus G-CSF as a mobilization strategy. We retrospectively analyzed clinical characteristics, PBSC collection and autologous stem cell transplantation parameters, and hematologic reconstitution data for 65 patients with relapsed or refractory DLBCL who underwent PBSC collection after mobilization with the modified R-DHAP protocol at our institution between 2002 and 2013. Data were evaluated for the overall cohort and with regard to the number of R-DHAP cycles received before PBSC collection. PBSC collection was performed after the first R-DHAP course in 32 patients (49%), after the second course in 30 patients (46%), and after the third course in 3 patients (5%). Sixty-three patients (97%) achieved the collection goal of ≥2.0 × 106 CD34+ cells/kg body weight. A significantly higher median CD34+ cell collection yield was achieved when cells were collected after the first R-DHAP course compared with after the second course (P < .01). A peripheral blood leukocyte increase of ≥1.0 × 109/L and a platelet increase of ≥20 × 109/L were observed by 11 days after ASCT. In our cohort, the modified R-DHAP regimen proved safe and feasible, showed an overall response rate (complete response, complete response unconfirmed, and partial response) of 66%, and allowed efficient mobilization of CD34+ cells for PBSC collection.

Fractionated High-Dose Cyclophosphamide and G-CSF: An Extremely Effective Chemo-Mobilization Modality In Patients With Multiple Myeloma

Background The optimal stem cell mobilization regimen for multiple myeloma (MM) is undefined. Most centers use either granulocyte-colony stimulating factor (G-CSF) alone (steady state strategy) or cyclophosphamide (CY) followed by G-CSF (chemo-mobilizing strategy). However, the impact of CY dose on stem cell yield and subsequent engraftment, and toxicity is unknown. We retrospectively analyzed our experience using fractionated high-dose CY and G-CSF as our preferred chemo-mobilization strategy in MM patients (pts) and its impact on the mobilization outcomes, engraftment and the observed toxicity. Methods Between 01/2000 and 12/2012, 220 chemo-mobilization attempts were undertaken. Among these, 62 pts (M=37, F=25) had MM (1st-line=54, relapsed=8) and all received high-dose CY and G-CSF. Median age was 56 (37-75) yrs. ISS stage was I (n=34), II (n=16), and III (n=12). Pre-transplant induction consisted of VAD or VAD-like chemotherapy (n=26), bortezomib(bor)/dexamethasone (dex) (n=15), thalidomide (thal) /dex (n=10), bor/thal/dex (n=10), and 1 received bor/lenalidomide/dex. Fifty-six received fractionated high-dose CY (5g/m2 divided in 5 doses of 1g/m2 q 3 hrs) whereas 6 received CY 50 mg/kg for 2 doses. G-CSF was given at a fixed dose of 300 µg SQ q 12 hrs. Results All 62 (100%) pts achieved a circulating CD34 count ≥20/µl which is the cut-off level at our center to proceed with apheresis. The median peak peripheral blood CD34+ cell count was 111.5 (21-575) cells/μL. Success rate of stem-cell mobilization defined as collection of more than 2x106 CD34+ cells/kg was 100%. Median stem cell collection yield was 15.9x106 CD34+ cells/kg. Moreover, 61 (98.4%) pts and 46 (74%) pts collected &gt;5x106 and &gt;10x106 CD34+ cells/kg, respectively. Only 4 (6.4%) pts required 2 apheresis sessions. Conversely, 40 (64.5%) pts required hospitalization for febrile neutropenia (n=38) or transfusion support (n=2) for a median of 4 (1-8) days. No one required intensive level of care and all recovered. Also, 17 (27.4%) pts required blood transfusions and 16 (25.8%) required platelets transfusion. Autografting was successfully performed in all pts using high-dose melphalan with a median time from mobilization to the first transplant of 31 (16-156) days and median infused CD34+ cells of 7x106/kg (3.1-15.3). All pts achieved successful hematologic engraftment with a median time for neutrophil engraftment (ANC ≥500/µL) of 11 days and platelet engraftment (platelet ≥20000/microliter) of 12 days. Conclusion Fractionated high-dose CY and G-CSF is a highly effective chemo-mobilization strategy in MM in terms of successful rate of mobilization (100%), efficiency of stem cell collection (high yield), and timely hematologic engraftment (100%). However, the relatively high-rate of hospitalizations for febrile neutropenia requires an assessment of its cost-efficiency as compared to new mobilization strategies using G-CSF and preemptive plerixafor. Disclosures: No relevant conflicts of interest to declare.

Factors affecting autologous peripheral blood hematopoietic stem cell collections by large-volume leukapheresis: a single center experience.

To evaluate factors affecting peripheral blood hematopoietic stem cell yield in patients undergoing large-volume leukapheresis for autologous peripheral blood stem cell collection. Data from 304 consecutive autologous peripheral blood stem cell donors mobilized with hematopoietic growth factor (usually G-CSF), associated or not with chemotherapy, at Hospital Israelita Albert Einstein between February 1999 and June 2010 were retrospectively analyzed. The objective was to obtain at least 2 × 106 CD34+ cells/kg of body weight. Pre-mobilization factors analyzed included patient's age, gender and diagnosis. Post mobilization parameters evaluated were pre-apheresis peripheral white blood cell count, immature circulating cell count, mononuclear cell count, peripheral blood CD34+ cell count, platelet count, and hemoglobin level. The effect of pre and post-mobilization factors on hematopoietic stem cell collection yield was investigated using logistic regression analysis (univariate and multivariate approaches). Pre-mobilization factors correlating to poor CD34 + cell yield in univariate analysis were acute myeloid leukemia (p = 0.017) and other hematological diseases (p = 0.023). Significant post-mobilization factors included peripheral blood immature circulating cells (p = 0.001), granulocytes (p = 0.002), hemoglobin level (p = 0.016), and CD34+ cell concentration (p < 0.001) in the first harvesting day. However, according to multivariate analysis, peripheral blood CD34+ cell content (p < 0.001) was the only independent factor that significantly correlated to poor hematopoietic stem cell yield. In this study, peripheral blood CD34+ cell concentration was the only factor significantly correlated to yield in patients submitted to for autologous collection.

Plerixafor Dosing and Administration in a Patient with Dialysis-Dependent Renal Failure

To report on the use of plerixafor in a patient with multiple myeloma and dialysis-dependent renal failure. A 38-year-old man with multiple myeloma and dialysis-dependent renal failure was evaluated for stem cell transplantation. Stem cell mobilization with 6 doses of granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/day yielded an inadequate maximum pre-apheresis CD34+ count of 5.6 cells/μL. The patient was treated with a postdialysis subcutaneous dose of plerixafor 160 μg/kg after 4 days of G-CSF therapy. After a single dose of plerixafor, the patient's pre-apheresis CD34+ count was 125.6 cells/μL. After 1 apheresis session, the stem cell collection yield was 5.33 x 10⁶ CD34+ cells/kg. There were no observed plerixafor toxicities. The patient underwent successful autologous stem cell transplantation. Times to neutrophil and platelet engraftment were 12 and 15 days, respectively. At 100-day follow-up, the patient's myeloma was in remission and he met all criteria for durable engraftment. Renal impairment is a common comorbidity in patients with multiple myeloma. Plerixafor is a chemokine receptor 4 antagonist approved for use to mobilize stem cells for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. To date, there is limited information on safe and effective dosing and administration of plerixafor in patients who are dialysis-dependent. This report describes the use of plerixafor in a patient with multiple myeloma and dialysis-dependent renal failure. Based on our experience, we are instituting a policy to administer plerixafor at Food and Drug Administration-approved renal adjustment doses in patients on hemodialysis, with dialysis sessions scheduled prior to plerixafor administration and repeated as necessary after apheresis and prior to subsequent plerixafor doses. If clinically feasible, dialysis should be held during the days required to collect stem cells.

Long-Term Cryopreservation of Autologous Stem Cell Grafts: Impact of Patient Age, Initial Collection, and Stem Cell Mobilization Regimen.

AbstractAbstract 1178 Background:Effectively cryopreserving hematopietic peripheral blood progenitor cells (HPC(A)) until time of transplant is critical for successful autologous stem cell transplant. It is important to demonstrate long-term HPC(A) viability and recovery and also to identify patient characteristics that may influence this. We evaluated HPC(A) products cryopreserved over 16 year period. We analyzed potential correlations between total nucleated cell (TNC) and CD34+ recovery and viability and patient age, initial collection, and impact of stem cell mobilization regimen. Method:Samples were obtained from expired patients, chosen based on storage duration but randomly selected in regard to patient and product characteristics; 23 samples were obtained from 18 patients. Five patients had 2 samples each; for duplicate samples, data were averaged (collection dates and thaw dates were similar). All HPC(A) products were frozen in autologous plasma and 10% DMSO, then stored in liquid phase or vapor phase nitrogen. Products were uniformly thawed and washed to remove DMSO. Analysis included 7-Amino-actinomycin D viability, TNC and CD34+ cell counts and recovery. Some samples had post-thaw CD34+ cell counts that exceeded pre-thaw count; for these, the recovery was set to 100%. Spearman rank correlations were used to analyze association between the different parameters. Wilcoxon rank sum test and analysis of covariance were used to compare patient groups. Result:Median patient age at time of stem cell collection was 54 (range 2–75) years. A majority of patients had lymphoma (61%) or multiple myeloma (22%). Most (56%) were mobilized using G-CSF+VP16, 33% with G-CSF alone, and 11% other. Samples were cryopreserved for a median of 8 years (range 1–16). Median (range) for total CD34+ × 106 collected was 547 (43-5845). Median (range) for CD34+/kg × 106 was 8 (1-59). Median (range) count/bag for TNC × 108 was 144 (37-285) and for CD34+ × 106 was 105 (8-805). Median (range) recovery and viability were 85% (32-213%), and 70% (46-85%) respectively for TNC; and 97% (16-359%) and 80% (61-98%), respectively for CD34+ cells.Pre- and post- thaw TNC and CD34+ counts were both highly correlated (r=0.95, p<.0001 in both cases – figures 1a and b). There was no significant association between TNC recovery and viability (r=-0.07, p=.79) or between CD34+ cell recovery and viability (r=-0.21, p=.41). Storage duration did not impact CD34+ recovery or viability (r=-0.01, p=.98 and -0.18, p=.47, respectively); or TNC viability (r=-0.13, p=.62). There was, however a significant positive correlation between the storage duration and TNC recovery (r=0.81, p<.0001).Age did not significantly impact TNC or CD34+ recovery (r=-0.05, p=0.86, and r=-0.26, p=0.29, respectively); however there was suggestion of negative impact on viability (r=-0.45, p=0.06 and r=-0.42, p=0.08, respectively, figures 1a and 1b). Overall, there did not appear to be a correlation between the initial TNC count/bag or total CD34+ cell dose on recovery or viability (r=0.29, r=-0.22, r=0.18, r=-0.38, respectively; all p>0.12). However, when patients were stratified according to total collection >25×106 CD34+ cells/kg or ≤25 × 106 CD34+ cells/kg, there was better %CD34+ cell count recovery between groups (p = 0.07, median recovery 81% for 13 patients with ≤25 × 106 CD34+ cells/kg and 100% for 5 patients with >25×106 CD34+ cells/kg). For mobilization regimen, there was no significant difference in TNC recovery or viability (p = 0.19 and p=0.76, respectively) or CD34+ viability (p = 0.53), however there was suggestion that CD34+ recovery was greater with G-CSF+VP16 (p=0.06, see figure 2), independent of storage time. Conclusion:Products cryopreserved for 16 years retain acceptable recovery and viability. Unexpectedly, storage duration positively correlated with TNC recovery, and CD34+ cell recovery of >100% was noted in several samples. Reasons for this are unclear, but are likely related to changes in enumeration method or use of methods validated for counting fresh cells. Patient age was suggested to negatively impact post-thaw HPC(A) viability. Our data also suggested that the mobilization regimen or the CD34+ cell collection yield may affect the CD34+ cell recovery, possibly reflecting differences in graft characteristics. The number of patients included is relatively small and these findings warrant further studies for validation. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Impact of constitutional polymorphisms in VCAM1 and CD44 on CD34+ cell collection yield after administration of granulocyte colony-stimulating factor to healthy donors

Background The number of CD34(+) cells mobilized from bone marrow to peripheral blood after administration of granulocyte colony-stimulating factor varies greatly among healthy donors. This fact might be explained, at least in part, by constitutional differences in genes involved in the interactions tethering CD34(+) cells to the bone marrow. We analyzed genetic characteristics associated with CD34(+) cell mobilization in 112 healthy individuals receiving granulocyte colony-stimulating factor (filgrastim; 10 μg/kg; 5 days). Genetic variants in VCAM1 and in CD44 were associated with the number of CD34(+) cells in peripheral blood after granulocyte colony-stimulating factor administration (P = 0.02 and P = 0.04, respectively), with the quantity of CD34(+) cells ×10⁶/kg of donor (4.6 versus 6.3; P < 0.001 and 7 versus 5.6; P = 0.025, respectively), and with total CD34(+) cells ×10⁶ (355 versus 495; P = 0.002 and 522 versus 422; P = 0.012, respectively) in the first apheresis. Of note, granulocyte colony-stimulating factor administration was associated with complete disappearance of VCAM1 mRNA expression in peripheral blood. Moreover, genetic variants in granulocyte colony-stimulating factor receptor (CSF3R) and in CXCL12 were associated with a lower and higher number of granulocyte colony-stimulating factor-mobilized CD34(+) cells/μL in peripheral blood (81 versus 106; P = 0.002 and 165 versus 98; P=0.02, respectively) and a genetic variant in CXCR4 was associated with a lower quantity of CD34(+) cells ×10⁶/kg of donor and total CD34(+) cells ×10⁶ (5.3 versus 6.7; P = 0.02 and 399 versus 533; P = 0.01, respectively). Conclusions In conclusion, genetic variability in molecules involved in migration and homing of CD34(+) cells influences the degree of mobilization of these cells.

High rate of stem cell mobilization failure after thalidomide and oral cyclophosphamide induction therapy for multiple myeloma

Novel agents are increasingly used during induction therapy for multiple myeloma (MM), but there is concern about their potential impact on stem cell mobilization. Regimens containing either thalidomide or cyclophosphamide have little or no impact on stem cell collection. In this retrospective review of 136 patients with newly diagnosed MM, we show that the combination of thalidomide and oral CY with dexamethasone (CTD) during induction therapy impaired stem cell mobilization substantially. Compared with VAD (vincristine, doxorubicin, dexamethasone) and a VAD-like induction regimen, the stem cell collection yield after CTD was decreased by 49% (median 5.0 vs 9.8 × 10(6) CD34+cells/kg, P<0.001). Following CTD, more patients failed to mobilize enough stem cells for one (25.4 vs 5.8%, P=0.002) or two (39.4 vs 15.9%, P=0.002) transplants. These results demonstrate that the combination of thalidomide and oral CY impairs stem cell mobilization and indicate that drugs with no previously reported relevant effect on stem cell mobilization can have a substantial impact when given in combination.

Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency: a Single Centre Experience.

Abstract 4362 BACKGROUND AND AIMSMultiple myeloma (MM) might be a cause a of the malignancy-related renal insufficiency, often present at diagnosis. Severity of it implicates further therapy. Patients with severe renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy regimens. The goal of this study was to evaluate the eligibility and efficacy of autologous hematopoietic stem cell transplantation (AHCT) in MM patients with concomitant renal insufficiency. 239 MM patients were treated in our department with high-dose chemotherapy followed by AHCT between 1993 and 2009. Twenty of them (8%) were also diagnosed with renal impairment. PATIENTS AND METHODS20 patients (8 women, 12 men), age 40-65 years (median 51) were enrolled. MM subtype at diagnosis was: IgG, n=14 (kappa-9, lambda-5); IgA kappa, n=1; light chain disease (LCD), n=4 (kappa-3, lambda-1); non-secretory, n=1. Chronic kidney disease (CKD) stage at MM diagnosis was 2-5 (median 3). One pt. was on chronic hemodialysis, two required plasmapheresis. Before AHCT pts. were treated with 1-4 (1) regimens, mainly VAD and CTD. 8/20 pts. received radiotherapy.Mobilization regimen was high-dose cyclophosphamide in 8 and IVE (iphosphamide, etoposide, epirubicin) in 12 cases. Stem cell collection yield was effective in all pts. (median 17.6 (1.9 - 44.7) x 10e6 CD34+ cells/kg). Disease stage at AHSCT: CR n=6, VGPR n=2, PR n=12. RESULTSRenal function measured before transplantation significantly improved due to MM treatment compared to that at diagnosis, p=0.008. CKD stage before transplantation equaled 1-4 (median 2). The only one patient who initially required hemodialysis became dialysis independent before AHCT.Conditioning regimen with melphalan (range 75-200mg/m2) was generally well tolerated. The median numbers of transplanted cells were following: NC 2.5 (1-7.6) x10e8/kg; CD34+ 7.9 (0.8-21.7) x 10e6/kg. All patients engrafted. Median regeneration time of granulocytes up to >0.5 G/l and of platelets to >50 G/l equaled 14 (12-19) and 14 (12-101) days, respectively. Transplant related mortality at day 100 was 0%. Mucositis, diarrhoea, bacterial and HSV infections were main complications after AHCT. Regeneration time, hospital stay, days of intravenous antibiotics or antifungal drugs administration and number of transfusion were comparable to pts. transplanted without renal impairment. No renal complications were observed. On the contrary creatinine clearance after transplantation showed trend towards further improvement compared to that before AHCT, p=0.07. The probability of overall (OS) and progression free (PFS) survival for studied group of pts. were 84% and 63%, respectively. Median observation time 2.3 years (0.1-12.5). CONCLUSIONSOur observation demonstrates that AHCT is an effective and well tolerated option for MM patients with mild or moderate renal insufficiency. Treatment before transplantation and also high-dose chemotherapy followed by AHCT may even improve renal function. No relationship between CKD and stem cell collection yield, engraftment or severity of post-transplant complications was observed in this group of patients. Disclosures:No relevant conflicts of interest to declare.