scholarly journals Peripheral Blood CD34+ Donor Chimerism Is Superior to CD3+ Donor Chimerism for Predicting Relapse Following Allogeneic Stem Cell Transplantation for Myeloid Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Tongted Das ◽  
Daniel North ◽  
Shaun Fleming ◽  
David Kliman ◽  
Andrew Spencer ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Research Funding ◽  
Lead Time ◽  
Donor Lymphocyte Infusion ◽  
Free Survival ◽  
Myeloid Malignancies ◽  
Donor Chimerism ◽  
Peripheral Blood Cd34 ◽  
Number Of Patients ◽  
Time To Relapse

Background: Disease relapse remains the main cause of mortality after allogeneic stem cell transplantation (allo-SCT) for patients with myeloid malignancies. Loss of donor chimerism (DC) is commonly used as a biomarker of impending relapse, which allows the initiation of pre-emptive therapies such as withdrawal of immunosuppression or donor lymphocyte infusion (DLI). Surprisingly, there are few if any direct comparisons of peripheral blood CD34+ and CD3+ DC as biomarkers to predict relapse. We hypothesized that loss of CD34+ DC may be a more direct measure of impending relapse given most myeloid malignancies express CD34. Methods: We prospectively measured peripheral blood CD34+ and CD3+ DC on days 30, 60, 90, 120 and 180 following allo-SCT for patients with AML (n=113) or MDS (n=23) transplanted at a single centre between July 2011 and November 2019. Chimerism analysis was performed using purified cell subsets isolated from 60 mL peripheral blood using PCR-based amplification of short tandem repeats (STRs). The goal of this retrospective analysis was to compare the value of CD3+ and CD34+ DC for predicting relapse. Institutional practice for CD34+ DC below 80% included a bone marrow biopsy to identify morphologic relapse and donor lymphocyte infusion. Statistical analysis was performed with R 3.5.2 (The R project for Statistical computing) or GraphPad (v8.2.0). Results: Overall, 41 of 136 (30%) patients had morphologic relapse at a median time of 153 days after allo-SCT (range 50-1742). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CD3+ and CD34+ donor chimerism for morphologic relapse is shown in Figure 1A. CD34+ DC outperformed CD3+ DC in all criteria, irrespective of the percentage chosen. Furthermore, a concurrent reduction in CD34+ DC was seen in almost all patients (14/16 at the 80% level) that had a fall in CD3+ DC. A fall in CD34+ DC below 80% was highly predictive for relapse, with a 5 year relapse free survival of only 17% compared with 80% for those that maintained DC > 80% for the first 180 days (Figure 1B). To determine the clinical utility of CD34+ DC, we measured the time to relapse in those patients that had a fall in DC without morphologic relapse at the time of DC measurement (Figure 1A). Based upon our institutional trigger of CD34+ DC < 80%, the median time to relapse was 49 days in 22 patients. In contrast, a CD34+ DC < 90% had a much longer time to relapse (71 days). However, this longer lead time would come at the price of unnecessary intervention in almost half of all patients as the PPV for CD34+ DC < 90% was only 55%. Loss of CD3+ DC had the longest lead time (> 70 days), however it was only useful up to 10 (24%) of all relapses. Finally, DLI administered for CD34+ DC < 80% maintained durable remission (> 12 months) in only 2 of 19 patients. Conclusion: This is the largest comparison of peripheral blood CD34+ and CD3+ DC following allo-SCT. Our results show that monthly monitoring of CD34+ DC in the first 6 months after allo-SCT is a more useful biomarker than CD3+ DC for predicting relapse in patients allografted for AML or MDS. The level of CD34+ DC chosen to trigger intervention should be guided by characteristics of the intervention such as toxicity and expected response time. Given the relative ineffectiveness of DLI for CD34+ < 80%, we suggest that 90% may provide greater time for immunologic responses. Figure Legend (A) Characteristics of different levels of CD3 and CD34 DC at any time in the first 180 days post-allo-SCT. Number of patients that fulfil the level in the total cohort of 136 patients. Number of patients before relapse indicates the number that do not have morphologic relapse at the time of DC measurement. Median days before relapse is shown for those patients. (B) Relapse free survival of patients according to CD34+ DC > 80% (blue line) or < 80% (yellow line) in the first 180 days. Disclosures Spencer: AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Celgene, Janssen and Takeda: Speakers Bureau; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria. Wei:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; MacroGenics: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Pfizer: Honoraria; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding.

scholarly journals Clonal Relapse Dynamics in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 611-611
Author(s):  
Clara Wienecke ◽  
Bennet Heida ◽  
Katrin Teich ◽  
Konstantin Büttner ◽  
Alessandro Liebich ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Lead Time ◽  
Hematopoietic Cell Transplantation ◽  
Limit Of Detection ◽  
Advisory Committees ◽  
Epigenetic Modifier ◽  
Time To Relapse ◽  
Time Point

Abstract Introduction The 2-year survival for AML patients relapsing after allogeneic hematopoietic cell transplantation (alloHCT) is <20%, independent of the choice of relapse-treatment. Relapse detection in its molecular state enables early interventions and possibly prevention of hematological recurrence of the disease. The role of measurable residual disease (MRD) monitoring for risk stratification has been described for pre and post-alloHCT MRD analyses. Yet, it remains unclear, if and by which lead-time NGS assessment can detect MRD before impending relapse. We hypothesize that the functional class of mutations determines the relapse kinetics in AML after alloHCT. Methods We identified mutations present at AML relapse after alloHCT by Illumina myeloid panel sequencing covering 48 AML associated genes. Peripheral whole blood samples were retrospectively collected before hematological relapse, with a minimum of one sample per patient at three months prior to relapse and if available, additional monthly samples. Amplicon-based NGS and bioinformatics error-correction were performed on those samples as described in Thol et al. 2018. Positive MRD was defined as MRD detectable above the limit of detection. In the last step, we performed polynomic curve interpolation to model relapse dynamics. Results MRD was assessed in 75 AML patients after alloHCT using 203 AML-related mutations present at the time of relapse, corresponding to a median of 2.7 trackable mutations per patient (range 1-7). In total, 305 MRD analyses were performed from peripheral blood (median 1.5 per mutation, range 1-5) prior to relapse. VAFs measured above the limit of detection (median LOD across all targets 0.0315) ranged from 0.0048-26% (median 1.3%). In 45 of 75 patients (60%), we detected MRD in at least one sample and one marker before relapse. Of those, 23 patients (51%) were MRD positive in all markers before relapse and 22 patients (49%) were MRD positive in some, but not all markers before relapse. The majority of MRD-positive patients (30 of 45) were first detected three or fewer months before relapse, whereas 15 (33%) of 45 patients were MRD positive more than 3 months before relapse. The median time to relapse from the first MRD-positive sample to relapse was 2.9 months (range 0.6-10.2). Among the 203 mutations found in relapse, 93 (46%) were detectable by MRD monitoring before relapse while the remaining 110 markers (54%) remained undetectable prior to relapse. Of note, 88 of those 110 markers (80%) were measured only once before relapse, indicating that frequent sampling increases the likelihood of MRD detection. Genes in which mutations were found mostly MRD-positive were TET2 (6 out of 6), ASXL2 (4 out of 5), SF3B1 (4 out of 5), and RUNX1 (7 out of 9). Mutations in WT1 (1 out of 13), NRAS (1 out of 8), FLT3-ITD (9 out of 29), and PTPN11 (1 out of 5) were among the most common MRD negative mutations before relapse. To assess clonal relapse dynamics, pre-relapse samples were assigned to the monthly interval that best matched the sampling time. If MRD was measured positive at one time point, all the following monthly intervals were considered MRD-positive, whether a sample was available for that interval or not. The fraction of positive samples from all samples per time point was plotted against time to relapse and the function was approximated by fifth-order polynomials. The percentage of patients being MRD positive increased markedly with shortened distance to relapse. Thus, 29% of patients were MRD positive at 3 months, 44% at 2 months and 66% 1 month prior to relapse. Summarized by functional gene classes, mutations in tumor suppressor genes and especially signaling genes showed a higher slope and thus a shorter lead-time to relapse than mutations in epigenetic modifier genes (Figure 2). Conclusion In summary, hematologic relapse can be detected in peripheral blood in 29, 44, and 66% of patients at 3, 2, and 1 months before relapse by NGS-MRD analysis, respectively. Mutations in epigenetic modifier genes show a higher fraction of MRD positivity before relapse than other mutations. In contrast, mutations in signaling genes show a shorter lead-time to relapse. Figure 1 Figure 1. Disclosures Ganser: Celgene: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Thol: Abbvie: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Jazz: Honoraria; BMS/Celgene: Honoraria, Research Funding. Heuser: BergenBio: Research Funding; Bayer Pharma AG: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Rapid Engraftment, Immune Cell Reconstitution and Sustained Donor Chimerism in Patients Receiving G-CSF Mobilized Peripheral Blood Stem Cells (PB-SC) from Related or Unrelated Donors Undergoing CD34 Enrichment with Mononuclear Cell (T cell) Addback in Children, Adolescents, and Adults with Malignant and Nonmalignant Diseases

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Jordan Milner ◽  
Cydney Nichols ◽  
Janet Ayello ◽  
Karen P. Seiter ◽  
Delong Liu ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Disease Status ◽  
Fixed Dose ◽  
Advisory Committees ◽  
Peripheral Blood Stem Cells ◽  
Donor Chimerism ◽  
Unrelated Donors ◽  
Grade Ii

Background: Graft versus host disease (GVHD) is a life-threatening complication following allogeneic stem cell transplantation (AlloSCT), which results from allo-reactive donor T-cells reacting against human leukocyte antigen (HLA) disparate host antigens. Despite the use of prophylactic immunosuppresants, 40 to 70 percent of patients undergoing HLA matched related and unrelated transplants will develop grade II-IV acute GVHD (Goker et al, Ex Hem, 2001; Nademanee, Blood, 1995; Rutuu et al, BMT, 1997).CD34+ enrichment of GCSF mobilized peripheral blood stem cells (PBSCs) obtained by apheresis is a method for T-cell depletion to reduce the risk of Grade II-IV aGVHD but unfortunately maybe concomitantly associated with delayed immune reconstitution, increased opportunistic infection and/or malignant relapse. To circumvent these latter complications, we previously demonstrated the results of a CD34+ enrichment with mononuclear cell (MNC) addback fixed at 2x105 CD3/kg of recipient weight in pediatric MUD recipients demonstrating rapid engraftment, robust immune reconstitution, and a low incidence of Grade II-IV aGVHD (Geyer/Cairo, BJH, 2012).More recently, we demonstrated a similar approach in children, adolescents, and young adults with high-risk SCD following familial haploidentical stem cell transplantation resulting in a rapid engraftment, probability of 6.7% of Grade II-IV aGVHD and 90% 1-year OS (Cairo et al, JAMA Peds, 2020). This approach of PBMNC addback with a fixed dose of 2x105 CD3/kg facilitated the infusion of additional NK, NKT, B, DC, DC2 cells at that same time (Chu/Cairo et al, ASH, 2020). Objective: To determine the safety, hematopoietic engraftment, probability of Grade II-IV GVHD following HLA related and unrelated PBSC transplantation following CD34+ enrichment with MNC cell addback (2x105 T-cell/kg fixed dose) in patients with malignant and non-malignant diseases. Design/Methods: Eligible patients were enrolled on study. Patients received individualized conditioning regimens determined by the PI stratified by disease, disease status, and donor source and received CD34+ enriched products processed by using the CliniMACSâ CD34+ Reagent System (Miltenyi Biotec, Bergisch Gladbach, Germany). The CD34+ cell product was either infused or cryopreserved and stored until time of transplantation. A target of 5x106 CD34+/kg recipient weight with a PBMNC fixed dose of 2x105 T cell CD3 dose/kg was infused as we previously demonstrated (Cairo et al, JAMA Peds, 2020). Patients were followed for safety, engraftment, donor chimerism, probability of Grade II-IV aGVHD and chronic GVHD. Results: Thirty-eight patients underwent HSCT with median age of 35.2 years (21 months to 71 years). Patients' disease status was as follows: complete remission (CR) 3 in 1 AML patient, CR2 in 8 AML patients, CR1 in 14 AML patients, CR2 in 4 ALL patients, CR1 in 2 ALL patients, PR in 1 MDS patient, Lymphohistiocytosis (n=1), Macrophage Activating Syndrome (n=1), Diamond Blackfan (n=1), Aplastic Anemia (n=2), Sickle Cell Disease (n=1), 1 CNL patient, CR2 in 1 Non-Hodgkins Lymphoma patient. Sixteen patients received allogeneic 10/10 HLA-matched unrelated donors, 5 from 9/10 HLA-matched unrelated donors, 12 from 6/6 HLA-matched sibling donors, 5 from related haplo donors. PB-HPC products contained 2x105 CD3/kg (±0.25 x 105), and 9.72x106 CD34/kg (±0.97 x106). After CD34 enrichment, the PB-HPC product processed was 76.09% CD34+ (±2.7%) (Fig. 1A) enriched with mean ± SEM log T cell depletion of 4.01 (±0.17) (Fig. 1B). The target HSCT dose per patient was 5x106 CD34/kg. Thirty-seven patients had myeloid engraftment and 32 patients had platelet engraftment with a median of 11 and 17 days, respectively. Six patients died prior to platelet engraftment - three due to multi-organ system failure following septic shock, two due to refractory disease, and one due to adenoviremia. Early and late peripheral blood chimerism was ³ 95% at 14- and 100-days following transplantation. The probability of grade II-IV aGVHD was 28.1% (CI95: 9.3-50.7) (Fig. 2). The probability of cGVHD was 4% (CI95: 0-63.5). Conclusion: This study demonstrates safety, rapid hematopoietic engraftment, sustained donor chimerism of CD34+ enriched PBSC products with MNC cell addback with a fixed 2x105 CD3/kg dose in alloSCT recipients with a low probability of Grade II-IV aGVHD.and cGVHD. Disclosures Seiter: Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Forma: Research Funding; Sun Pharma: Research Funding; Amphivena: Research Funding; Roche: Research Funding; AbbVie: Speakers Bureau; Alexion: Speakers Bureau; Onconova: Research Funding. Flower:Lentigen Technology Inc/Miltenyi Biotec: Research Funding. Cairo:Miltenyi: Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1962-1962
Author(s):  
Sandhya R. Panch ◽  
Brent R. Logan ◽  
Jennifer A. Sees ◽  
Bipin N. Savani ◽  
Nirali N. Shah ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Time Interval ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Peripheral Blood Cd34 ◽  
Cell Counts ◽  
Cd34 Cells

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

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

Blood ◽  
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 &gt;500 x 106/L and independence from platelet transfusion in the preceding 7 days with a count &gt;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.

RICE/ICE Is an Effective PBSC Mobilising Regime in Patients with Aggressive Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5513-5513
Author(s):  
Edward Wilson ◽  
Rachel Pawson ◽  
Kathleen Beston ◽  
John Smyth ◽  
Chris Hatton
Keyword(s):  
Stem Cell ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
Large Cell ◽  
Aggressive Lymphoma ◽  
Low Grade ◽  
Peripheral Blood Stem Cells ◽  
Peripheral Blood Cd34 ◽  
Number Of Patients ◽  
Blood Stem Cells

Abstract RICE/ICE is an effective re-induction chemotherapy regime for patients with relapsed or refractory aggressive lymphoma prior to autologous stem cell transplantation. There is however a paucity of data on its effectiveness as a peripheral blood stem cell mobilising regime. We present data on its use in 23 patients, age 50 ± 15 (mean ± SD), with relapsed (n=16) or primary refactory (n=7) lymphoma (DLBCL (n=15), mantle cell (n=1), high grade transformation of follicular lymphoma (n=5), Hodgkins lymphoma (n=1), Anaplastic large cell lymphoma (n=1)). RICE (Rituximab 375mg/m2 (day 1), Etoposide 100mg/m2 (days 1–3), Carboplatin 5x(CrCl+25)mg/m2 (day 2) and Ifosphamide 5000mg/m2 (day 2)) was administered as re-induction chemotherapy (4 patients did not receive Rituximab) along with Filgrastim 10mcg/kg/day from day 5 until collection. Apheresis was attempted on day 15 in those patients (n=18) achieving a peripheral blood CD34+ve cell count greater than 10x103/ml. Peripheral blood stem cells were collected on a Gambro Cobe Spectra cell seperator processing a median of 2.5 blood volumes by standard protocols. Eight patients achieved a successful collection in the first apheresis session, six patients required a single further collection on day 16 and four patients required further collections on days 16 and 17. The median CD34+ve cell dose collected was 5.01x106/kg (range 0.5x106/kg − 17.4x106/kg) with only 2 patients achieving inadequate collections (0.5x106/kg and 1.37x106/kg). In total 70% (16 of 23) of patients successfully achieved PBSC collections of greater than 2.0x106/kg. The group of patients that failed to mobilise was not predictable in terms of known adverse markers such as marrow involvement, underlying low grade lymphoma or previous chemo/radiotherapy. In conclusion successful PBSC collection was achieved in the majority of patients treated with RICE/ICE although the number of patients is small and larger numbers will be required to confirm these results.

Detailed Investigation On Characteristics of Japanese Patients with Chronic Phase CML Who Achieved a Durable CMR After Discontinuation of Imatinib – an Updated Result of the Keio STIM Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2788-2788 ◽  
Author(s):  
Eri Matsuki ◽  
Yukako Ono ◽  
Koharu Tonegawa ◽  
Masatoshi Sakurai ◽  
Hiroyoshi Kunimoto ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Copy Number ◽  
Treatment Duration ◽  
Japanese Patients ◽  
The Other ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Free Survival ◽  
Number Of Patients

Abstract Abstract 2788 Background and Purpose: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for patients with chronic myelogenous leukemia (CML). It can induce durable hematologic, cytogenetic and molecular response, leading to a marked improvement of progression-free survival (PFS). On the other hand, long-term discontinuation of TKIs has recently been investigated by many groups. Our study was designed to confirm whether TKI could be safely discontinued in Japanese patients who have maintained complete molecular response (CMR) for at least 2 years, and to identify possible factors associated with prolonged drug-free survival (DFS), including immunologic profile. The effect of imatinib discontinuation in terms of quality of life (QOL) was also assessed. Method: Adult patients with CML who have sustained CMR (defined as negative quantitative and qualitative PCR of bcr-abl in the bone marrow) for more than 2 years were enrolled in the study. Treatment with imatinib or one of the other TKIs was initiated if the peripheral blood quantitative PCR (TMA method) value exceeded 100 copies. Lymphocyte subset analysis was performed before discontinuation of the drug, and at 6 months after discontinuation or re-induction of the drug in case of relapse. In 6 patients, WT-1 specific cytotoxic T lymphocyte (CTL) frequency was also assessed before, 3 and 6 months after drug discontinuation. QOL analysis was performed using SF-36 questionnaire before, 2 months and 1 year after discontinuation of imatinib. Patients: 41 patients were enrolled in the study, among which 40 patients were analyzed. The median age of the patients was 54 (range 28 – 83) years old. The Sokal risk score was low in 24 (60%), intermediate in 10 (25%) and high in 3 (7.5%) patients. The median time on imatinib treatment was 98 (range 24–126) months and the median duration of CMR was 49.5 months (range 24–106). Results: The median follow-up of the patients at the time of this analysis was 15.5 months (range 2–18). Treatment was restarted in 18 patients (45%), and the estimated DFS rate at 12 months was 55.4% (Fig 1). In 5 patients, imatinib was commenced again, whereas 13 patients were re-treated with dasatinib. All but one patient restored CMR after commencing TKIs. Among various factors including age, previous interferon treatment, duration of imatinib treatment, duration of CMR, time until CMR, sex, cytomegalovirus serology and Sokal risk score, duration of CMR was identified as a significant factor associated with prolonged DFS on univariate analysis (p=0.027), the difference which was also significant upon multivariate analysis (p=0.014). Regarding lymphocyte subsets in the peripheral blood, no significant changes were observed in CD4, 19, 56, ab TCR, gd TCR, CD4/CD25 positive cell population, but, there was a significant increase in the proportion of CD8 positive T cells among those who relapsed and those who did not (2.4% vs −2.4%, p=0.04). There was a trend for increased proportion of WT-1 specific CTL in patients who were restarted on TKI therapy. QOL scores of both physical and mental domains did not differ significantly with the discontinuation of imatinib or re-initiation of treatment, although symptoms such as facial puffiness or muscle cramping were markedly decreased with discontinuation. There was also no difference in the patients' QOL according to the choice of drug used for re-treatment. Altogether 6 patients had fluctuating PCR copy number during follow-up, of which 2 were restarted on treatment. Others have maintained low copy number or have returned to negative during follow-up. Due to the small number of patients, no specific clinical factors or immunophenotypes associated with sustained low count PCR were identified. Conclusion: Sustained CMR was achieved in a substantial proportion of patients who had been in CMR for over 2 years. All patients restarted on TKI treatment remained sensitive to treatment. Longer time in CMR was identified as a significant factor related to sustained CMR in our patient population. Increase in CTL may also correlate with the necessity to restart treatment. Longer observation period and increased number of patients is necessary to draw a concrete conclusion, and to identify the role of immunologic profiles relative to persistence of CMR. Disclosures: No relevant conflicts of interest to declare.

scholarly journals An Oncology Simulation Model to Estimate 10-Year Progression-Free Survival and Stem Cell Transplantation for Frontline, Stage III or IV Classical Hodgkin Lymphoma Based on the 5-Year Update of the ECHELON-1 Trial: A United States Perspective

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2440-2440
Author(s):  
Tycel Phillips ◽  
Kristen Migliaccio-Walle ◽  
Kristina S. Yu ◽  
Brian Bloudek ◽  
Nicholas Liu ◽  
...  
Keyword(s):  
Simulation Model ◽  
Research Funding ◽  
Progression Free Survival ◽  
Stage Iii ◽  
Publicly Traded ◽  
Free Survival ◽  
Annual Prevalence ◽  
Number Of Patients ◽  
Relapsed Disease

Abstract Objectives Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the most common frontline (1L) regimen for patients with stage III or IV classical Hodgkin lymphoma (cHL), but about 30% of patients with stage III or IV cHL have refractory or relapsed disease after ABVD treatment. Based on the 5-year update of the ECHELON-1 trial, patients on 1L brentuximab vedotin, doxorubicin, vinblastine and dacarbazine (A+AVD) continued to demonstrate a robust and durable progression-free survival (PFS) improvement vs ABVD with a 32% reduction in the risk of progression or death (HR=0.681, nominal P=0.002). Our objective was to estimate the future number of patients with cHL who are alive and progression-free over 10-years with 1L A+AVD, based on the 5-year follow-up results from ECHELON-1. Methods An oncology simulation model, from the United States perspective, was developed with a 1-month cycle length that estimates population-level outcomes based on annual prevalence of cHL, considering disease incidence, treatment patterns, PFS, and overall survival of commonly used treatment regimens for stage III or IV cHL. Incidence of cHL was derived from the 2019 Surveillance, Epidemiology, and End Results (SEER) Program, assuming 95% of HL is classical of which 41% is stage III or IV. To populate the base case model, treatment patterns following 1L use of ABVD (64.5%) and positron emission tomography (PET)-adapted therapy (35.5%) were varied over time and compared to A+AVD (24%). For every model cycle, patients who experienced disease progression on 1L therapy discontinued therapy and transitioned to second-line (salvage) therapy. The transition from second-line therapy to transplant is also included in the model based on patient eligibility. Model inputs were informed by 1) real-world treatment utilization; 2) treatment-specific clinical trial data, including ECHELON-1 with 5-year PFS rates of 75.3% for ABVD (95% CI: 70.0, 85.0) and 82.2% for A+AVD (95% CI: 71.7, 78.5); and 3) expert clinicians' opinions. Annual prevalence of patients living progression-free with cHL in the 1L setting with each prescribing scenario was estimated for 10 years (year 2031) with and without the availability of A+AVD. Results The annual number of newly diagnosed patients with stage III or IV cHL at 10 years in 2031 was estimated at 3,586. The number of patients alive and progression-free in the 1L setting was 19,494 without A+AVD and 19,660 with A+AVD (Δ+166, 0.85% increase) in 2031. Overall, for every 100 patients prescribed A+AVD, it was predicted that an additional 6.5 patients per year achieved at least 5 years PFS and 4.2 to 4.7 fewer patients per year required a stem cell transplant (SCT), based on the 70% to 80% of eligible patient proceeding to SCT, respectively. Conclusions The durable PFS improvement of A+AVD vs ABVD in the 5-year follow-up data from ECHELON-1 resulted in increasing the number of patients with stage III or IV cHL who remain progression free for greater than 10 years and reducing future SCTs, based on this oncology simulation model for cHL. The significant improvement in PFS observed in the 5-year ECHELON-1 trial may translate to fewer patients with cHL developing primary refractory or relapsed disease and reduce the need for additional therapies including SCT. Disclosures Phillips: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy. Migliaccio-Walle: Seagen, Inc: Consultancy. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Bloudek: Seagen, Inc: Consultancy. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Burke: Beigene: Consultancy, Speakers Bureau; Verastem: Consultancy; Kymera: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive Biotechnologies: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy; Kura: Consultancy; Epizyme: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau; AbbVie: Consultancy.

scholarly journals Outcomes after Donor Lymphocyte Infusion for Insufficient Donor Chimerism Following Hematopoietic Cell Transplantation for Non-Malignant Disorders

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1969-1969
Author(s):  
Carter Biewen ◽  
Angela R Smith ◽  
Jakub Tolar ◽  
Weston P Miller
Keyword(s):  
Epidermolysis Bullosa ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Donor Lymphocyte Infusion ◽  
Hla Typing ◽  
Junctional Epidermolysis Bullosa ◽  
Donor Chimerism ◽  
Cell Dose ◽  
The Impact

Abstract Background: Little is reported of the utility of donor lymphocyte infusion (DLI) following HCT for non-malignant disorders (NMD). We describe outcomes after DLI for insufficient donor chimerism after HCT in a large NMD cohort. Patients/Methods: We queried the Institutional BMT Database for patients with NMD receiving DLI for insufficient post-HCT donor chimerism. HLA typing, graft selection and conditioning were per institutional guidelines. The use, timing and dosing of DLI was at the discretion of the treating physician. Donor chimerism values on the myeloid fraction of peripheral blood at pre-DLI and most-recent time-points were reviewed. Patients were considered best DLI responders if donor chimerism improved (pre-DLI to most-recent) and most recent chimerism was ³ 80%. Results: Twenty-three patients (43% female) were identified. Table 1 shows patient, disease, transplant and DLI characteristics. The median zenith chimerism post-HCT (but pre-DLI) was 84% (IQR, 39 - 99%), observed at a median 28 days post-HCT. The median chimerism just prior to first DLI was 40%. The median time to first DLI was 90 days. Patients underwent a median 2 cycles (IQR, 2 - 3; maximum, 5) of DLI; the median cumulative per-patient CD3+ dose was 11.5 x 106/kg. Post DLI, two patients developed aGvHD and 2 patients developed cGvHD. Five patients (22%) were best DLI responders. At a mean 3.6 years post-HCT, they retained mean chimerism of 94% (mean increase from pre-DLI of 37%). Of the 18 non-best responders (78%), median chimerism at last follow-up was 10% (IQR, 2 - 25%). Seven patients underwent repeat HCT. Best response to DLI did not depend on HCT total nucleated cell dose, donor relatedness, serotherapy agent of HCT regimen, chimerism prior to DLI, or total DLI CD3+ dose. Best responders tended to have undergone myeloablative conditioning, be HLA-matched to the donor and receive first DLI later post-HCT (median 102 days, versus 83 days). Conclusions: In a large NMD cohort undergoing DLI after HCT, sustained high donor chimerism response was observed in 22%. Ongoing analyses aim to assess those with intermediate response (many of whom also enjoy improved or stable NMD), as well as the impact of peri-DLI immune suppression on outcomes. Table 1. Patient, Disease and Transplant Characteristics. ID Dx Age (y) at HCT Conditioning/ Serotherapy Donor / Graft HCT TNC(x 108 /kg) Days# to DLI DLI@ CD3+ (x106 /kg) % Chimerism Pre/MRFU aGvHD (grade) / cGvHD Re-HCT? Survival (y#) Notes / Cause of Death 1 ALD 8.1 MA / ATG R / BM 2.16 508 6 92 / 100 n/n n A (10) SD 2 ALD 8.3 NMA / C R / BM 3.17 73 9 59 / 27 n/n n A (6) SD 3 ALD 8.4 NMA / C R / BM 3.97 51 45 44 / 23 n/n n A (4.6) SD 4 ALD 9.9 NMA / C R / BM 2.13 44 17 43 / 17 n/n n A (7.2) SD 5 HLH 18 NMA/ Unk U / BM 1.94 102 1 75 / 100 Y(4)/n n D (0.6) Viral; Resp Failure 6 HLH 1 NMA / C U / BM 9.39 181 3 3 / 4 n/n Y D (1.9) Sepsis 7 Hurler 2.5 MA / ATG R / BM 5.05 193 16 67 / 58 n/n n A (8.3) SD 8 Hurler 1 MA / C R / BM 4.25 305 1 64 / 80 n/n n A (6.7) SD 9 IPEX 1.3 NMA / Unk U / BM 4.99 160 13 44 / 56 n/n n A( 6.4) SD 10 JEB 0.5 NMA / ATG U / BM 5.22 81 6 25 / 13 n/n n D (0.4) Sepsis 11 RDEB 2.8 NMA / ATG R / BM 6.21 274 11 17 / 25 n/n n A (2.1) SD 12 RDEB 6.3 NMA / ATG R / BM 7.28 167 Unk 17 / 6 n/n n A (3.1) SD 13 RDEB 0.9 NMA / ATG U / BM 9.91 98 16 12 / 87 n/n n A (2.7) SD 14 RDEB 3.3 NMA / ATG R / BM 3.53 48 16 10 / 0 n/n Y A (1.6) SD 15 RDEB 0.9 NMA / ATG R / BM 3.35 90 65 40 / 100 n/Y n A (1) SD 16 RDEB 4.9 NMA / ATG R / BM 4.27 133 65 41 / 25 n/n n A (0.8) SD 17 RDEB 0.5 NMA / ATG R / BM 5.5 85 30 71 / 45 n/n n A (0.7) SD 18 SCD 9.1 NMA / ATG U / BM 3.19 34 0.5 0 / 0 n/n n D (13.7) Progressive SCD 19 SCD 10.2 NMA / ATG U / PBSC 0.13 57 12 69 / 4 n/n Y A (10) Rejected re-HCT 20 Thal 2.3 NMA / ATG R / BM 3 84 Unk 15 / 0 n/n Y A (7.3) E, SD 21 Thal 2.8 NMA / ATG U / PBSC 0.22 48 1 40 / 0 Y(2)/Y Y D (2.2) cGvHD 22 Thal 1.7 NMA / C U / PBSC 0.17 69 5 11 / 2 n/n Y A (7.6) E, SD 23 Thal 2.6 MA / ATG R / BM 6.23 159 Unk 17 / 4 n/n Y A (5.3) E, SD # = time referenced to HCT; @ = cumulative CD3+ cell dose; ALD = adrenoleukodystrophy; HLH = hemophagocytic lymphohistiocytosis; IPEX = immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; JEB = junctional epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa; SCD = sickle cell disease; Thal = thalassemia; y = years; MA = myeloablative; NMA - non-myeloablative; ATG = anti-thymocyte globulin; C = alemtuzumab; Unk = unknown; R = related; U = unrelated; BM = marrow; PBSC = peripheral blood stem cell; TNC = total nucleated cell dose; Pre = just prior to DLI; MRFU = most recent follow-up; n = no; Y = yes; A = alive; D = dead; SD = stable disease; E = engrafted. Disclosures No relevant conflicts of interest to declare.

Rituximab Purging and Maintenance Improves Progression Free Survival but Not Overall Survival In Patients with Relapsed or Resistant Follicular Lymphoma Prior Receiving An Autologous Transplant

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3567-3567 ◽  
Author(s):  
Ruth Pettengell ◽  
Norbert Schmitz ◽  
Christian Gisselbrecht ◽  
Graeme Smith ◽  
William N Patton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peripheral Blood ◽  
Research Funding ◽  
Progression Free Survival ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Post Transplant ◽  
Autologous Transplant

Abstract Abstract 3567 Autologous transplantation significantly improves the progression free survival (PFS) and overall survival (OS) of patients with relapsed or resistant follicular (rFL) lymphoma compared with chemotherapy alone (Schouten H, et al. J Clin Oncol 2003;21:3918–27). Small phase II trials suggest, that rituximab (R) given peritransplant further improves survival outcome. Whilst the role of maintenance R post chemotherapy in FL is established, the benefit and safety of maintenance R following autologous transplant is unknown. In this randomised prospective study the efficacy and safety of R as in vivo purging pretransplant and as maintenance treatment immediately post transplant was assessed. From Oct 1999 to Apr 2006, 280 of a planned 420 R naïve patients with rFL in first (n=16), second (n= 222) or third remission (n=41) who achieved either a complete remission (n=83) or a very good partial remission (n=196) to induction chemotherapy, with limited bone marrow infiltration (<25% B-lymphocytes) underwent a single randomisation in a 2 × 2 design to R purging 375 mg/m2 weekly × 4 (RP) before high-dose therapy with BEAM conditioning (HDC) and maintenance R 375 mg/m2 every 3 months for 2 years (RM). The primary endpoint of the study was PFS. All analysis is by intention to treat. The median age was 51 years (range: 26–70), and baseline characteristics were well balanced between groups. On average patients were 44.1 (range 3.4–463.8) months from diagnosis with 79.3% having 2 lines of therapy and 15% three lines of prior therapy. Patients were equally distributed between low, intermediate and high FLIPI scores. Pretransplant 70% of patients were in PR and 30% in CR. Fifty seven patients failed to mobilise peripheral blood stem cells. Nineteen patients withdrew, 5 due to toxicity, 9 were ineligible. In the 196 (70%) patients transplanted, neutrophil engraftment > 0.5 × 109 /L was prompt, median 14.3 days (range 10–115) and platelets > 50 × 109/L,median 25.1 days (range 9–190). Time to engraftment and early or late toxicities did not differ significantly between the groups apart from a lower neutrophil count at 3 months in patients on maintenance. No graft failures or late neutropenia was reported. Transplant related mortality was 0.5%. Only 3 infection related deaths have been reported post 100 days. Two hundred and seventeen patients are alive on continued follow-up. Median follow-up is 6.4 years. PFS at 5 years was 62.9% for patients receiving RP + RM versus 37.6 % for patients receiving no R (logrank PFS; p=0.004; HR 0.76, 95%CI: 0.66 – 0.93). OS at 5 years was 79.5% % versus 78.4 % for patient receiving RP + RM versus no R (logrank PFS; p>0.1). Multivariate analysis was not able to define a high or low risk patient group. R in vivo purging and maintenance results in superior PFS compared to no R. R does not adversely affect peripheral blood stem cell harvesting or engraftment and maintenance R post transplant is safe. The impressive OS suggests that relapsed FL patients can be effectively salvaged post R purging and maintenance. R Purging + R Maintenance R Maintenance R Purging No R Pt number 69 69 72 70 Median PFS NR@ 6.4 y 7.23 y 4.03 y 3.34 y 5y PFS 62.9 % 56 % 46 % 37.6 % 5y OS 79.5 % 80.5 % 84.8 % 78.4 % Disclosures: Pettengell: Roche: Honoraria. Schmitz:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding. Walewski:Roche: Honoraria, Research Funding. Geisler:Roche: Research Funding. Kimby:Roche: Honoraria, Research Funding. Goldstone:Roche: Honoraria, Speakers Bureau.

Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: PK Guided IV Busulfan Dose Intensity Results in Improved Event Free Survival

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2006-2006
Author(s):  
Uday Popat ◽  
Borje S Andersson ◽  
Roland Bassett ◽  
Stefan Ciurea ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Research Funding ◽  
High Dose ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
High Group ◽  
Hematopoietic Stem ◽  
Free Survival

Abstract Abstract 2006 Background: Allogeneic hematopoietic stem cell transplantation (HCT) is an effective treatment for patients with advanced myelofibrosis. Myeloablative regimens have produced a high rate of morbidity and mortality. Reduced intensity conditioning (RIC) with allogeneic transplantation is being investigated with the goal of reducing non-relapse mortality. There is concern that this benefit might occur at expense of a higher relapse rate. In 2006 we initiated a study of RIC regimen of fludarabine 40mg/m2 (days −5, −4, −3 −2) and IV busulfan 130mg/m2 (day −3,−2). In the first 14 patients (the Bu-low group), 9 patients relapsed. We hypothesized that high dose PK guided IV busulfan would decrease relapse rate without substantially increasing non relapse mortality, thereby improving event free survival (EFS). The next 19 patients received an increased intensity of busulfan (Bu-high group), using pharmacokinetic dose adjustment. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Patients received IV busulfan dose to a target daily AUC of 4000 μmol/L × 4days (days −5, −4, −3 −2) Fludarabine 40mg/m2 (days −5, −4, −3 −2). Average busulfan dose in Bu-high group was 473 mg/m2 (range 304–886 mg/m2) or 10.8 mg/kg, and it was 260mg/m2 or 6.5mg/kg in Bu-low group. Both cohorts of patients received tacrolimus and mini methotrexate as graft versus host disease prophylaxis and similar supportive care. Thymoglobulin 2.5 mg/kg × 3 (day −3,−2 and 1) was given to all patients receiving an unrelated donor graft. Results: Between 1/2006 and 12/2010, 33 consecutive patients with myelofibrosis were treated including 14 in the Bu-low and 19 in the Bu-high groups. Patients and disease characteristics were similar for the two treatment groups. There were 16 males and 17 females with a median age of 59 (range 27–70). Eighteen patients had primary MF, 8 post PV MF and 7 Post ET MF. Based on Lille criteria, 17 patients had intermediate risk disease and 16 had high risk disease. Eleven patients had splenectomy prior to transplant; remaining 22 patients had enlarged spleen at the time of transplant. Twenty patients had mutated Jak 2. Median peripheral blood CD 34 count was 54/μl (range 1–16426/μl). Karyotype was abnormal in 12 patients and diploid in 21. Donors were matched siblings for 12 patients, matched unrelated for 17, and one antigen or allele mismatched unrelated for 4 patients. Stem cell source was marrow in 4 and peripheral blood in 29. Circulating blasts were present in 17 patients. All patients engrafted with a median time to neutrophil engraftment of 13 days (0–27) days and a median time to platelet engraftment of 18 (0–105) days. Cumulative incidence of acute GVHD was 28% and chronic GVHD 35% (limited 7%, extensive 28%). Cumulative incidence of non relapse mortality was 10% with overall 3 treatment related deaths: 1 in Bu-high group and 2 in Bu-low group (p=0.44). With a median follow up of 1.6 (0.2–5) years, current EFS (p=0.02) and the cumulative incidence of relapse (p=0.04) were significantly different between Bu-high and Bu-low groups, while overall survival (OS) was not (0.28). Two year estimates for the Bu-high and Bu-low groups are as follows: EFS: 69% and 29%; OS: 87% and 71%; cumulative incidence of relapse: 26% and 57%. Multivariate analysis showed that Bu-high dose (HR 0.25; p=0.01) and peripheral blood CD 34 count >100 μl (HR 3.56; p=0.02) were significant predictors of EFS. Conclusion: Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non relapse mortality, resulting in better EFS in patients with MF. Disclosures: Popat: Otsuka: Research Funding. Andersson:Otsuka American Pharmaceuticals, Inc.: Consultant for Clinical Protocol Development. Nieto:Otsuka: Research Funding. Qazilbash:Otsuka: Research Funding. Champlin:Otsuka: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document