scholarly journals Impact of Two Different Types of Rabbit ATG on Immune Reconstitution and Overall Results after Allogeneic Hematopoetic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Children

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Camille Feltesse ◽  
Karima Yakouben ◽  
Mony Fahd ◽  
Marie Ouachee ◽  
Lou le Mouel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Immune Reconstitution ◽  
Lymphoblastic Leukemia ◽  
Effector Memory ◽  
Joint Models ◽  
Advisory Committees ◽  
Cd8 Cells ◽  
Stem Cell Source ◽  
Significant Difference

Introduction Thymoglobulin® and Grafalon® are 2 polyclonal rabbit anti-thymocyte globulin (ATG) used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent graft rejection and graft-versus-host disease (GvHD). Differences in manufacturing lead to different types and concentrations of antibodies in each product. Few studies compare their effects on post-transplant immune reconstitution: indeed, the latter is essential to prevent post-transplant infections as well as relapse (in case of hematological malignancies). Methods We conducted a retrospective study on children or adolescents who received a first unrelated allo-HSCT for an Acute Lymphoblastic Leukemia (ALL) between 2007 and 2018, in the department of pediatric hematology of the Robert Debré Hospital in Paris, France. During this time period, 2 types of ATG were used: Thymoglobulin® at 7.5mg/kg or Grafalon® at 60mg/kg. We included patients with a B or T phenotype ALL aged 2 to 18 years at the time of HSCT indication. Stem cell source could be from unrelated matched or mismatched bone marrow, peripheral blood or cord blood. All patients received a myeloablative conditioning regimen consisting of 12 grays total body irradiation and etoposide (60mg/kg). We compared patients for engraftment, counts of total lymphocytes, B and T lymphocytes, T CD4+ and CD8+ lymphocytes and their sub-types (naïve, effector memory, central memory and effector memory RA+), regulatory T cells, NK cells, and compared lymphocyte proliferation assays at 1, 3, 6 and 12 months after transplant. We used joint models of longitudinal and survival data to further analyze evolution of total lymphocytes, B and T cells, T CD4+ and T CD8+ cells, and NK cells. Finally, we compared clinical outcomes between the 2 groups. Statistical analyses were performed according to EBMT guidelines (Iacobelli, 2013). Results 76 children were included: 23 received Thymoglobulin® and 53 received Grafalon®. Stem cell source was peripheral blood or bone marrow for 61 patients and cord blood for 15 patients. Initial characteristics of patients, disease status and HSCT were similar between the two groups except for the median total nucleated cells and CD34+ progenitor cells of the graft, that were significantly higher in the Grafalon® group. We found a delayed cumulative incidence of engraftment in patients who received Grafalon® compared to those who received Thymoglobulin®: 29 days [interquartile range 22-36] versus 22 days [19.5-29.5], p=0.004. We observed significantly higher counts of total and T CD4+ lymphocytes 1 month after transplant in patients who received Thymoglobulin® as compared to those who received Grafalon®: 238/mm3 [172-466] versus 137/mm3 [51-306] respectively (p=0.005), and 40/mm3 [31.5-70.5] versus 16/mm3 [2.5-41.5], respectively (p=0.011). No differences in immune cell population counts were found 3, 6 and 12 months after transplant (figure 1). However, joint models found no difference in the evolution of lymphocyte subsets analyzed depending on the ATG used, except a non-significant difference in slopes over time for CD8+ cells (p=0.13). In patients given Thymoglobulin® compared to those given Grafalon®, we found a higher proliferation in response to stimulation by CD3 3 month after HSCT (CD3 index 20.4 [12.4;41] versus 5.9 [3.3;6.4] respectively, p=0.0039), and a higher proliferation in response to stimulation by adenovirus (ADV) antigen 1 year after HSCT (ADV index 78.6 [58.8;163.1] versus 15.7 [2.8;59.3] respectively, p=0.027). We found no effect of ATG type on overall survival (OS), disease-free survival (DFS), treatment-related mortality and chronic GvHD. In a multivariate analysis, we observed no effect of the type of ATG on OS and DFS. Conclusions We found a higher count of total and T CD4+ lymphocytes 1 month after unrelated allo-HSCT for ALL in children who received Thymoglobulin® at 7.5mg/kg compared to those who received Grafalon® at 60mg/kg. From 3 months after HSCT, we found no difference in immune reconstitution. Joint models for longitudinal data and survival found no significant difference in evolution of the lymphocyte subsets analyzed. Clinical outcomes were similar between the two groups. However, we compared an intermediate dose of Thymoglobulin® to a high dose of Grafalon® that is not still the standard in clinical practice. A prospective study comparing Thymoglobulin® to a lower dose of Grafalon® would be needed. Disclosures Baruchel: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Bellicum: Consultancy. Dalle:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum: Consultancy, Honoraria; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

BK Virus-Specific T Cell Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3425-3425
Author(s):  
Eduardo Espada ◽  
Ann E. Woolley ◽  
Jason Avigan ◽  
Edouard Forcade ◽  
Maria V.D. Soares ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Board Of Directors ◽  
Cd4 T Cells ◽  
Research Funding ◽  
Clinical Disease ◽  
Effector Memory ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Cd8 Cells

Abstract Introduction: BK virus (BKV) seropositivity is highly prevalent (80-90%) in healthy adults, but BKV rarely causes significant clinical disease. However, immunologic control of BKV is often compromised after allogeneic hematopoietic stem cell transplantation (HSCT) and BKV reactivation can cause clinical disease, including hemorrhagic cystitis, in 5-68% of patients in the first year after HSCT. Immune reconstitution of BKV-specific T cells after HSCT has not been well defined, and the role of BKV-specific T cells in response to clinical infection has not been studied. Methods: From the DFCI 2010-2011 HSCT cohort (Rorije et al, BBMT 2014), 33 adult patients were selected who had urinary symptoms, were tested for urine BKV by PCR, and were diagnosed with BKV disease (cases; n=16) or did not have BKV reactivation (controls; n=17). Cases and controls were matched for cyclophosphamide use, acute GvHD and stem cell source. BKV-specific T cells were analyzed in 180 prospectively cryopreserved peripheral blood mononuclear cells (PBMC) samples (average 5.5/patient) across several timepoints (pre-HSCT and 1, 3, 6, 9, 12, 18 and 24 months post-HSCT) using cytokine flow cytometry (CFC). PBMC were stimulated for 6 hours with overlapping 15-mer peptides derived from BKV LT and VP1 proteins in the presence of brefeldin A, monensin and anti-CD28/49d. Results were compared with no-pepmix negative controls and Staphylococcal enterotoxin B positive controls. After stimulation, cells were stained with fluorochrome-conjugated antibodies specific for CD3, CD4, CD8, CD45RA, CCR7, CD57, CD107a, IFNγ, TNFα, IL-2, perforin (PERF) and granzyme B (GZMB). Laboratory assessments were blinded to clinical disease status. Results: Median age of the cohort was 51 years (IQR; 39-61); 79% were male and acute GvHD occurred in 64%. Conditioning included cyclophosphamide in 46% and ATG in 24%; cell source was peripheral blood stem cells in 81%, cord blood in 15% and bone marrow in 3%. Median time from HSCT to BKV testing was 60 days (23-181); median time to first positive test was 79 days (26-196) in BKV+ cases. Median duration of symptoms was 53 days (11-92) in cases, compared to 5 days in controls. The percentage of patients with BKV-specific T cells across timepoints is summarized in Figure 1. The frequency of BKV-specific degranulating (CD107a) T cells peaked at 6mo, where they could be detected in 37.5% and 58.3% of patients by reactivity of CD8+ and CD4+ T cells, respectively. Detection of BKV-specific T cells producing any cytokines (cytokine+) peaked at 9 mo (CD8+ in 19% and CD4+ in 38.1% of patients). BKV-specific IFNγ+, IL-2+, and TNFα+ T cells all peaked at 12mo after HSCT. Subsequently, detection of BKV-specific CD8+ T cells declined sharply while BKV-specific CD4+ T cells were maintained at higher levels 24 months after HSCT. Comparing BKV-specific immune responses in cases and controls, IFNγ+ CD8+ cells reconstituted faster in patients with clinical disease (first detected at 3 months vs. 9 mo), and were present in more patients at 9 months: 41.7% vs. 11.1%. A similar trend was noted for IL-2+ CD8+, IFNγ+ CD4+, and IL-2+ CD4+ T cells (Figure 2). BKV-specific CD8+ T cells were predominately central memory (CM) and terminally differentiated effector memory and their cytokine profile increased gradually after transplant; 19% produced at least two cytokines at 1 mo, compared to 71% at 12 mo. BKV-specific CD4+ T cells were predominately CM and effector memory and their cytokine profile also increased after transplant; 3.5% produced at least two cytokines at 1 mo, compared to 35% at 12 mo and 69.5% at 24 mo. PERF and/or GZMB were detected in 45-74% of BKV-specific CD107a CD8+ cells. CD107a CD8+ cells also produced IFNγ. Conclusion: BKV-specific T cells gradually reconstitute in the first 9 months after allogeneic HSCT. 30-40% of patients with clinical symptoms and 50-60% of patients with confirmed BKV disease had detectable BKV-specific T cells but BKV-specific immunity recovers more rapidly in patients with BKV disease. As CD8 and CD4 BKV-specific immunity recovers, T cells gradually become more functional with a memory phenotype. Our cohort is currently being expanded to assess the correlation between the development and expansion of BKV-specific T cells and clinical outcomes. Disclosures Koreth: kadmon corp: Membership on an entity's Board of Directors or advisory committees; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; amgen inc: Consultancy; LLS: Research Funding; prometheus labs inc: Research Funding; millennium pharmaceuticals: Research Funding. Armand:Otsuka: Research Funding; BMS: Consultancy, Research Funding; Infinity: Consultancy; Sequenta: Research Funding; Roche: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding. Soiffer:GentiumSpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees.

Allogenic Transplantation in Lymphomas: A Focused Analysis On Aggressive Lymphomas and Factors Predictive of Outcome in a Series of 179 Pts Treated At John Theurer Cancer Center.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3120-3120
Author(s):  
Anthony R Mato ◽  
Kathryn Waksmundzki ◽  
Tania Zielonka ◽  
Ewelina A Protomastro ◽  
Theresa Amatucci ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Board Of Directors ◽  
Cox Regression ◽  
Cancer Center ◽  
Advisory Committees ◽  
Stem Cell Source ◽  
Cell Source ◽  
Refractory Lymphoma ◽  
Donor Source

Abstract Abstract 3120 Introduction: Chemo-immunotherapy (i.e. rituximab combinations) has clearly had a significant impact on the outcome of all B-cell NHL both in terms of PFS and OS. However in the relapse/refractory setting a large proportion of pts still do very poorly especially in aggressive subtypes including DLBCL and MCL. Salvage therapy followed by HDT-ASCT in relapsed DLBCL remains the standard, though pts with early failures (<1y) and/or prior exposure to rituximab still show dismal results (CORAL data). In MCL the use of HDT-ASCT in the relapse setting is debated given the frequency of chemo-resistance leading to poor results even in second CR. The use of allogeneic transplantation was developed based on observations c/w with a clear GVL effect in NHL as illustrated by pts going into remission after DLI injections. The development of non-myeloablative approaches has allowed expansion of use of allogeneic BMT in relapsed/refractory NHL. We report here one of the largest series (179 consecutive pts) with relapsed/refractory lymphoma focusing on overall survival and outcome predictors. Methods: Utilizing Kaplan-Meier survival and Cox regression methods, we report on the outcome of 179 consecutive pts with relapsed/refractory lymphoma who underwent allogeneic stem cell transplantation at the John Theurer Cancer Center between 1995–2012. The primary study endpoint was overall survival (OS) assessed by chart and SSDI database review. Secondary study endpoints included examination of the association between overall survival and allogeneic stem cell source, donor source, development of GVHD, pre-transplant chemo-sensitivity and prior failure to HDT-ASCT (second transplant). The proportional hazards assumption was met for this analysis. Results: Survival data on 179 pts (median age 48, range 20–71) were analyzed, representing 86 deaths and 5720 total months at risk (median follow up=12.3 months). Baseline characteristics included: ECOG PS (med 1, range 0–2), diagnosis (25% DLBCL, 21% HD, 20% MCL, 13% FCL, 13% PTCL, 8% other), donor source (50% matched SIB, 31% MUD, 19% mismatched MUD), stem cell source (73% PB, 23% BM, 6% Cord) and prior autologous SCT (38%). The median OS for the entire cohort was 31.2 months. OS KM curves by selected aggressive NHL subtypes are represented in Figure 1. We performed COX regression analyses to address outlined secondary endpoints. In univariate analyses statistically significant inferior outcomes were associated with the use of mismatched unrelated donor (HR 1.4, p=.01, Figure 2), bone marrow donor stem cells vs. PBSCT (HR=1.7 p=.04), pre-transplant stable/refractory disease (HR 1.8, p=.03), absence of cGVHD (HR=4.7, p<.001) and presence of acute GVHD (HR 2.8, p=.001). No difference in OS was detected whether pts had undergone allogeneic SCT as a second transplant (med time between auto/allo=20.9 months) following relapse after auto SCT (HR 1.14, CI .75–1.73, p=.5). Conclusions: This series represents a large cohort of poor risk, relapsed/refractory lymphoma pts treated consecutively with allogeneic stem cell transplantation over a > 10-year period at our institution with the following observations: Disclosures: Mato: Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Goldberg:Eisai: Speakers Bureau. Feldman:Allos: Speakers Bureau; celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau; Merck: Speakers Bureau. Goy:Milennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; J & J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2186-2186
Author(s):  
Alissa Visram ◽  
Natasha Kekre ◽  
Christopher N. Bredeson ◽  
Jason Tay ◽  
Lothar B. Huebsch ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Infection Rates ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Significant Difference

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

scholarly journals Early Immune Reconstitution after Hematopoietic Stem Cell Transplantation for Adolescents and Adults with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3907-3907
Author(s):  
Loïc Vasseur ◽  
Florence Morin ◽  
Corinne Pondarré ◽  
Florian Chevillon ◽  
Aude-Marie Fourmont ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Immune Reconstitution ◽  
Normal Values ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Stem Cell Source ◽  
Cell Source ◽  
Adolescents And Adults

Abstract Introduction Allogeneic hematopoïetic stem cell transplantation (HSCT) is the only established curative therapy for patients (pts) with sickle cell disease (SCD). It is mostly performed in children 1, due to higher risk of graft-versus-host disease (GVHD) and transplant related mortality in adults. Different approaches have been developped to improve tolerance of transplant in adults: use of reduced intensity conditioning (RIC) regimens 2 and intensive immunosuppression to avoid GVHD. Here, we have studied the impact of such approaches on immune reconstitution in adolescents and adults transplanted for SCD. Patients and methods We report 39 transplants in adolescents and adults, performed in Saint Louis hospital from 2008 to 2020: 25 were matched related transplants (MRT) and 14 haplo-identical related transplant (HRT). In MRT, conditioning was myeloablative (MAC) in 15 pts (busulfan, cyclophosphamide, rabbit anti-thymoglobulin (ATG) 20 mg/kg) and non myeloablative (NMA) in 10 pts (alemtuzumab 1 mg/kg, 3 Gy total body irradiation (TBI)). In MAC transplants, stem cell source was bone marrow and post-transplant immunosuppression was methotrexate and cyclosporine. In NMA transplants, stem cell source was peripheral blood cells with post-transplant immunosuppression by sirolimus. In the 14 HRT, the conditioning was reduced (cyclophosphamide, thiotepa, fludarabine, 2 Gy TBI, ATG 4.5 mg/kg), stem cell source was bone marrow and GVHD prophylaxis was ensured by post-transplant cyclophosphamide (100 mg/kg), sirolimus and mycophenolate mofetil. Results Median age at transplant was 17 years (y) old (range (r) 14-39). With a median follow-up of 3.6 y, the 2-y overall survival and survival without SCD were 97% (IC95%: 0.92-1) and 92% (IC95%: 0.83-1) respectively: no event after MRT, 1 death of GVHD and 2 graft rejections after HRT. The acute GVHD grade II-IV rate was 33%: 21% after HRT, 13% after MAC MRT and 0% after NMA MRT. Chronic GVHD occured in 3 pts (8%): severe in 1 HRT and mild in 2 MAC MRT. At 6 months, the blood chimerism evaluated in the 36 patients alive without rejection, was more often mixed (5 to 95% of donor) after NMA MRT (100%) versus MAC MRT (40%, p = 0.003) and HRT (18%, p &lt; 0.001). Total lymphocytes (TL) counts increased rapidly in HRT and MAC MRT with a normalization from 3 months post-transplant. In contrast, NMA MRT experienced a slower recovery: at 6 months, median count was 1039/mm3 (r 463-1767) compared to 2071/mm3 (r 882-5985, p = 0.002) after MAC MRT and 2382/mm3 (r 676-3978, p = 0.005) after HRT. After NMA MRT, TL counts remained lower than normal values up to 12 months with a median of 1195/mm3 (r 870-3210) (Figure 1A). HRT displayed a rapid normalization of CD4 counts with a 3-month median count of 645/mm3 (r 350-1076) higher than reported after MRT (p &lt; 0.001). Evolution of CD4 counts was similar after NMA and MAC MRT. They were lower than normal values during the first 12 months: median 364/mm3 and 388/mm3 respectively at 12 months (p = 0.25) (Figure 1B). From 3 months post-transplant, CD8 counts reached normal values after MAC MRT (314/mm3, r 108-2175) and were superior to normal after HRT (1335/mm3, r 66-4529), with a significant difference between HRT and MRT (p = 0.003). After NMA MRT, there was a trend for lower 3-month CD8 counts compared to MAC MRT: median of 107/mm3 (r 18-631, p = 0.08). CD8 counts remained under normal values after NMA MRT up to 12 months post-transplant (Figure 1C). From 3 to 6 months, CD4 and CD8 were mostly memory, with only 3.2% (r 0.1%-20.6%) and 6.2% (r 2.1%-11.2%) of CD45RA+ CCR7+ naïve CD8+ and CD4+ respectively. In the 3 groups NK cell counts reached normal values after 3 months. B lymphocytes counts normalized in the first months post-transplant except for patients who received rituximab for EBV reactivation. From 3 to 6 months, B lymphocytes were mostly naive: 98% of CD27- (r 92%-99%). Gammaglobuline levels were normal from 3 months in the 3 groups. Twelve (31%) pts were treated for a CMV and 6 (15%) for an EBV reactivation. No patient had CMV or adenovirus disease, or post-transplant lymphoproliferative disorder. Infections according to transplant types are detailed in figure 1D. Conclusion NMA MRT were associated with a delayed CD4 and CD8 recovery probably due to alemtuzumab. As previously reported 3, HRT displayed a rapid immune reconstitution. Despite use of serotherapy in the three modalities of transplant, the rate of viral infections remained acceptable without severe episode. Figure 1 Figure 1. Disclosures Pondarré: ADDMEDICA: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Boissel: CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria.

scholarly journals PD-1-Mediated T Cell Exhaustion Is Prevalent Among Patients with MPN-Associated Myelofibrosis Independent of JAK1/2 Inhibition

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5487-5487
Author(s):  
Ivo Veletic ◽  
Taghi Manshouri ◽  
Graciela M. Nogueras González ◽  
Sanja Prijic ◽  
Joseph E. Bove ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Spleen Size ◽  
Advisory Committees ◽  
Cd8 Cells ◽  
Circulating T Cells

Abstract Background: Primary myelofibrosis (PMF), post-polycythemia vera MF (post-PV MF) and post-essential thrombocythemia MF (post-ET MF) are characterized by expansion of the neoplastic clone and by progressive bone marrow (BM) fibrosis. Like in other hematologic malignancies, in most patients with MF the immune system is significantly deregulated: MF patients' plasma cytokine and chemokine levels are markedly increased and their normal T cell subset distribution is significantly altered. Although treatment with the Janus kinase (JAK)-1/2 inhibitor ruxolitinib significantly decreases cytokine/chemokine levels, reduces spleen size, and improves symptoms and quality of life, it does not reverse BM fibrosis nor does it halt the propagation of the neoplastic clone. The T cell immune checkpoint programmed cell death protein-1 (PD-1) promotes immune tolerance by binding to the tumor's cell surface PD-1 ligand (PD-L1). Whereas the importance of T cell-mediated immune tolerance in MF has been documented and trials evaluating clinical benefits of PD1/PD-L1 checkpoint inhibition are ongoing, little is known about the effect of ruxolitinib on PD-1 expression in T cell subsets. Therefore we systematically analyzed MF patients circulating T cells' surface marker expression prior to and during ruxolitinib treatment. Methods: Peripheral blood cells were obtained from well-characterized PMF, post-PV MF and post-ET MF patients prior to and during the course of treatment with ruxolitinib (n=47) and, as control, from age-matched healthy donors (n=28). The proportion of PD-1-expressing CD4+ and CD8+ cells was assessed using multiparameter flow cytometry. Naïve, central memory, effector memory, and effector T cell subsets were defined based on CD45RO and CD27 cell surface antigen expression. Results: A significantly high number of circulating T cells co-expressing CD4+/PD-1+ and CD8+/PD-1+ was found in MF patients compared to age-matched healthy individuals (5.3±4.1% vs. 3.4±1.7%, P=0.028; 7.1±4.4% vs. 3.8±2.3%, P=0.001). Whereas MF patients' naïve T cells harbored an increased number of cells co-expressing CD8+/PD-1+ (P=0.007), but not CD4+/PD-1+, their T central memory cells had a high proportion of cells co-expressing CD4+/PD-1+ and CD8+/PD-1+ (P<0.001; P<0.001). Similarly, a high proportion of circulating PD-1+ T effector memory cells (P<0.001; P<0.001), and T effector cells (P=0.013; P<0.001) was found in MF patients compared to the same cell subsets in healthy age-matched individuals. The proportions of PD-1+ T cells significantly correlated with LDH level and DIPSS score (CD4+ T cells), monocyte count (CD8+ T cells), and total leukocyte count and spleen size (both subsets). Remarkably, the percentage of PD-1+ cells within naïve and central memory CD8+ T cell populations was significantly higher in MF patients with circulating blasts (P=0.036). To determine the effects of ruxolitinib administration, we performed repeated flow cytometry analyses on MF patients' T cells prior to and during treatment (median duration: 4.3 years). Overall, no significant change in PD-1 expression levels in any of the different T cell subsets was detected over the entire treatment period. However, a significant reduction in percentage of cells co-expressing CD4+/PD-1+ and CD8+/ PD-1+ compared to treatment baseline (4.4±0.4% vs. 7.6±2.0%, P=0.011; 6.3±0.6% vs. 10.4±2.7%, P=0.021) was found in patients whose spleen size was reduced after 6 months of treatment. Conclusions: In patients with MF, circulating T cells express high levels of PD-1. While not restricted to a particular stage of T cell differentiation, the correlation between PD-1-expressing T cells and distinct clinical parameters suggests that increased PD-1 levels might induce immune exhaustion in T cell subsets in different ways. Although ruxolitinib significantly inhibits the JAK1/2 signaling pathway in a variety of hematopoietic cells, thereby lowering cytokine/chemokine levels in almost all MF patients, treatment with ruxolitinib did not affect PD-1 expression nor did it alter its distribution among the T cell subsets. Yet, the proportion of PD-1-expressing CD4+ and CD8+ cells was markedly reduced in patients who experienced a superior response to ruxolitinib as assessed by significant spleen size reduction. How disease burden and MF microenvironment affect PD-1 expression in T cells of patients with MF warrants further investigation. Disclosures Verstovsek: Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1641-1641 ◽  
Author(s):  
Elias Jabbour ◽  
Kathryn G. Roberts ◽  
Koji Sasaki ◽  
Yaqi Zhao ◽  
Chunxu Qu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

Reduced Intensity Versus Conventional Myeloablative Conditioning (RIC vs. MAC) Allogeneic Stem Cell Transplantation (allo-SCT) for Patients with Acute Lymphoblastic Leukemia (ALL): A Survey from the Acute Leukemia Working Party of EBMT

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 793-793 ◽  
Author(s):  
Mohamad Mohty ◽  
Myriam Labopin ◽  
Tapani Ruutu ◽  
Alois Gratwohl ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Negative Impact ◽  
Therapeutic Option ◽  
Lymphoblastic Leukemia ◽  
Working Party ◽  
High Dose ◽  
Adult Age ◽  
Stem Cell Source ◽  
Significant Difference

Abstract The exact role of RIC allo-SCT for adult patients with ALL is still under considerable debate. While the use of such so-called nonmyeloablative or RIC regimens has emerged as an attractive modality to decrease transplant-related mortality, toxicity might represent only one aspect of the problem, since ALL encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen may have a negative impact on long-term leukemic control. In this multicenter retrospective study, the outcomes of 601 adult (age at transplantation >45 y.) patients with ALL who underwent transplantation in complete remission (CR) with an HLA–identical sibling donor, were analyzed according to 2 types of conditioning: RIC in 97 patients, and standard MAC (or high-dose) in 504 patients. Both groups were comparable in terms of gender, CR status (CR1 and CR2), interval from diagnosis to allo-SCT, and recipient/donor CMV serostatus. Patients in the RIC groups were older (median 56 y. vs. 50y in the MAC group; P<0.0001), Most of the patients in the MAC group received high dose TBI (80%), while the majority of the RIC regimens included either low-dose TBI or were ATG+chemotherapy-based regimens. The majority of patients (88%) from the RIC group received a PBSC graft. In the MAC group, the stem cell source consisted of bone marrow in 42% of patients. With a median follow-up of 13 months (range, 1–127), the incidences of grade II-IV and grade III-IV acute GVHD were: 35%, 14%, and 28%, 10% in the MAC and RIC groups respectively (P=NS). The cumulative incidence of non-relapse mortality at 2 years (NRM) was 32% (MAC) vs. 22% (RIC) (P=0.04). The cumulative incidence of relapse at 2 years was 30% (MAC) vs. 42% (RIC) (P=0.0007). However, the latter differences did not translate into any significant difference in term of leukemia-free survival (LFS) at 2 years: 38% (MAC) vs. 37% (RIC) (P=0.42). In multivariate analysis for LFS, the status at transplant was the only factor associated with an improved LFS (p<0.0001, RR=0.55, 95%CI, 0.42–0.72). The results of this retrospective registry based study suggest that RIC regimens may reduce NRM rate after allo-SCT for adult ALL when compared to standard MAC regimens, but with a higher risk of disease relapse and no impact on LFS. The latter represent promising findings, since patients who received RIC are likely to have serious comorbidities, which led the transplantation center to choose RIC, and surely most of these patients would not have received a standard allo-SCT in most institutions. Therefore, RIC allo-SCT for adult ALL (>45 y.) may represent a valid therapeutic option when a conventional standard conditioning is not possible, warranting further prospective investigations.

scholarly journals Older Age As a Prognostic Factor for Overall Survival for Multiple Myeloma Patients Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2144-2144
Author(s):  
David M. Cordas Dos Santos ◽  
Rima M. Saliba ◽  
Romil Patel ◽  
Qaiser Bashir ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Older Age ◽  
Stage Ii ◽  
Advisory Committees ◽  
Post Transplant ◽  
Cart Analysis ◽  
Significant Difference

Abstract Background High-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is considered the standard of care for newly diagnosed, transplant-eligible multiple myeloma (MM) patients. Due to improvements in induction, stem cell mobilization, and dose adjustment of the conditioning regimen, auto-HCT is increasingly used in older MM patients, with several retrospective analyses showing similar clinical outcomes compared to younger patients. Methods To further confirm these results, we performed a single-center retrospective analysis of MM patients undergoing auto-HCT between January 2006 and December 2016. Patients were divided into two groups: older (> 70 years) and younger (≤ 70 years). Results 1128 patients (182 older, 946 younger) were included in this analysis. Patient characteristics are summarized in the attached Table. More patients (59% vs. 45%, p = 0.01) in the older cohort had ISS stage II or III disease. Older cohort was more likely to receive reduced-dose melphalan (140 mg/m²) as conditioning regimen (32% vs 3%, p = <0.0001). There was no significant difference in high-risk cytogenetics, induction regimens, and response to induction, or post-transplant maintenance between the older and younger cohorts. The overall median follow-up among survivors was 49 months in the older and 52 months in the younger group. One-hundred-day non-relapse mortality (NRM) was 2/182 (1.1%) and 6/946 (0.6%) (p = 0.5) in the older and younger groups, respectively. However, 1-year NRM was significantly higher in the older vs. younger cohort (7 /182 (4%; unknown 3, pneumonia or respiratory failure 4) vs. 9/946 (1%; unknown 2, pneumonia or respiratory failure 4, cardiac failure 3), HR 4.1, p = 0.005). Post-transplant, 75 (41%) and 431 (45%) achieved complete remission (CR) in the older and younger groups, respectively (p = 0.29). There was no significant difference in the rate of disease progression post-transplant between older (31%) and younger (30%) groups (p = 0.3). The 5-year progression free survival (PFS) was 24% and 37% in the older and younger groups, respectively (HR 1.3, p = 0.02). Similarly, 5-year overall survival (OS) was 56% and 73% in the older and younger groups (HR 1.8, p = <0.001). In univariate analyses, age > 70 years, high-risk cytogenetics, serum creatinine level > 2 mg/dl and ISS stage III were associated with worse PFS and OS. In contrast, melphalan 200 mg/m² for conditioning and achievement of CR after induction therapy were associated with better PFS and OS. These 6 factors were studied in multivariate analyses using a classification and regression tree (CART) method. In CART analysis for PFS, ISS stage II or III, and high-risk cytogenetics were associated with shorter PFS. Similarly, in CART analysis for OS, older age (> 69 years), ISS stage II or III, and high-risk cytogenetics were associated with a shorter OS. Conclusion In this large single-center analysis, there was no difference in 100-day NRM, CR rates and the risk of progression after auto-HCT between the older and the younger patients. However, older age was associated with a shorter PFS and OS due to increased NRM. On multivariate CART analysis, ISS stage II or III and high-risk cytogenetics were associated with a worse PFS and OS, while age > 69 years was associated with a worse OS only. The impact of comorbidities on NRM is being evaluated in ongoing analyses. Disclosures Lee: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Abbvie: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Thomas:Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Array Pharma: Research Funding. Orlowski:BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Millenium Pharmaceuticals: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

scholarly journals Outcome of Patients with Myelofibrosis Relapsing after Allogeneic Stem Cell Transplant: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1958-1958
Author(s):  
Donal McLornan ◽  
Richard Szydlo ◽  
Anja van Biezen ◽  
Linda Koster ◽  
Evgeny Klyuchnikov ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Median Survival ◽  
Research Funding ◽  
Working Party ◽  
Active Management ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Number Of Patients ◽  
Significant Difference

Abstract Background: Over the last decade, there has been a significant increase in the number of patients with Myelofibrosis (MF) undergoing allogeneic stem cell transplantation (SCT). However, scarce information exists on the outcome and management of those patients who relapse following SCT. Moreover, the management of relapse occurring post-SCT is often heterogeneous and ranges from palliation to intensive salvage approaches. We therefore conducted a retrospective EBMT registry analysis of adult MF patients who relapsed following first SCT episode. Results: A total of 1216 adult patients (997 (82%) with Primary MF (PMF) and 219 (18%) with secondary MF (sMF)) underwent 1st allogeneic SCT between 2000 and 2010. A total of 251 patients from this cohort (206 with PMF and 45 with sMF) had conformed relapse ≥ day 30 after HSCT and were included in the analysis. Within this relapse cohort, there were 163 males and 88 females; median age was 55 years old (range 21.5-70 years). A total of 84 patients (33%) had received Myeloablative Conditioning (MAC) and 167 patients (67%) Reduced Intensity Conditioning (RIC). Regarding donor type, there were 123 matched siblings (49%) and 128 unrelated donors (51%). Acute GVHD (aGVHD) status was available for 243/251 (97%) patients; no aGVHD was evident in 143 patients, Grade I-II aGVHD 76 patients, Grade III-IV aGVHD 22 patients and 2 patients with aGVHD ungraded. The median time to relapse after SCT was 7.1 months (range 1-111 months). The median Overall Survival (OS) from the time of relapse was 17.7 months (95% Confidence Intervals 11-24). Collectively, there was a significant difference in survival outcome for those relapsing > 7.1 months post-SCT (median survival 30.3 months post relapse) compared to those relapsing within 7.1 months following the initial SCT episode (median survival 7.9 months post relapse; p<0.001). Absence of aGVHD or grade I aGVHD only was associated with a trend towards improved survival following relapse compared to those with Grade II-IV aGVHD (p=0.12). For PMF, disease duration prior to SCT did not significantly affect outcome post relapse. Heterogeneous practice existed as regards management of the relapse episode, with considerable variation in median survival (MS) estimates. 47 patients received Donor Lymphocyte Infusions (DLI) alone (MS 76 months); 21 had chemotherapy alone (MS 23 months) whereas 14 patients had DLI combined with chemotherapy (MS 13.6 months). As regards 2nd allografts: 53 patients underwent 2nd allograft alone (MS 23.6 months) and 26 underwent DLI and 2nd SCT (MS 53.9). In 90 patients active management -if any- was not documented (most likely many were palliative) but represented a very poor risk group with a MS of only 4.8 months. Overall, there was a significant improvement in OS post relapse for those undergoing 2nd SCT (n=79) versus those who did not have a 2nd SCT (n=172; p=0.019). Conclusions : This analysis represents the first study to define the outcome of MF patients who undergo relapse following allogeneic SCT. Treatment of relapse presents huge challenges and the heterogeneous management strategies highlighted above reflects current practice where approaches range from palliation through to intensive chemotherapy and 2nd SCT. It is clear from this analysis that early relapse has a much worse prognosis than those who relapse later than 7.1 months post-SCT. There is a definite survival advantage for those who undergo DLI and/or a 2nd SCT procedure, although we acknowledge that those patients undergoing a 2nd SCT represent a highly selected group who are fit enough to undergo such intervention. Moreover, how relapse management practice will change in the era of novel therapies such as JAK inhibitors to bridge towards 2nd SCT is currently unclear and requires evaluation in prospective studies. Disclosures McLornan: Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Biosimilar G-CSF Versus Originator G-CSF for Autologous Peripheral Blood Stem Cell Mobilization: A Comparative Analysis of Mobilization and Engraftment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3345-3345 ◽  
Author(s):  
Julie Stakiw ◽  
Waleed Sabry ◽  
Mohamed Elemary ◽  
Mark J. Bosch ◽  
Pat Danyluk ◽  
...  
Keyword(s):  
Stem Cell ◽  
Length Of Stay ◽  
Board Of Directors ◽  
Similar Efficacy ◽  
Stem Cell Mobilization ◽  
P Value ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Significant Difference ◽  
Cell Mobilization

Abstract Biologic agents are among the fastest-growing classes of therapeutic products. A biosimilar therapeutic product is defined as one that is similar to an already licensed reference product in regard to quality, safety, and efficacy and is often priced more competitively (Expert Committee on Biological Standardization, 2009; Publicover, et al., 2013). In 2016, the Saskatchewan Cancer Agency effectively changed from a granulocyte colony-stimulating factor (G-CSF) brand name product (Neupogen®) to a biosimilar (Grastofil®) for stem cell mobilization prior to autologous stem cell transplants (ASCT). However, because its efficacy in this setting is currently unknown, many institutions continue to use the brand name product. To address this, we reviewed patient charts and compared the efficacy of CD34+ collection in 170 patients who received Neupogen® and 47 patients who received Grastofil® between 2012 and 2018. Additionally, we analyzed efficacy of mobilization with both G-CSF products either alone or in combination with chemotherapy, patients requiring more than one apheresis day and requirement for Plerixafor®. Time to engraftment, and length of stay in hospital post ASCT were used as clinical efficacy parameters. This analysis is important to ensure that patient outcome is not compromised upon use of Grastofil® as opposed to the already approved reference, Neupogen®. The increased use of biosimilars would allow for decreased costs and more sustainable healthcare. Results Neupogen® and Grastofil® had similar efficacy for stem cell mobilization as 92.4% of the patients harvested with the brand name had a successful harvest compared to 100% of the patients given the biosimilar. A successful harvest is defined as a collection of ≥2x106 CD34+ cells for patients planned for one stem cell transplant and ≥4x106 CD34+ cells for patients planned for two transplants. Additionally, the two drugs did not display a statistically significant difference in Plerixafor requirement in a situation with low CD34+ count. Amongst all 217 patients, 25.9% of patients given Neupogen® required Plerixafor® as compared to 23.4% of Grastofil® patients. As seen from Table 1, by using the Wilcoxon test to compare the efficacy of Neupogen® and Grastofil® without chemotherapy for stem cell mobilization, there was no significant difference seen with a p-value of 0.53. Similarly, in patients mobilized with chemotherapy in addition to either Neupogen® or Grastofil®, similar efficacy was seen between the groups given a p-value of 0.95. There was no statistically significant difference between the patient groups with respect to requiring more than 1 day of apheresis. 59.4% of patients mobilized with Neupogen® required more than 1 apheresis day compared to 76.9% of Grastofil® patients (p = 0.11). Similarly, of the Neupogen® and Grastofil® groups mobilized with chemotherapy, 42.5% and 38.1%, respectively, required more than one apheresis day which was not statistically different (p = 0.71). Table 2 presents the engraftment data which also suggests that the two drugs behave with similar efficacy in this respect. Length of stay in hospital post autologous stem cell transplant was an additional variable analyzed. Again, there was no significant difference in length of stay between patients who received Neupogen® (median=18.5 days, IQR=17.0-21.0) or Grastofil® (median=19.0 days, IQR =17.0-22.0) without chemotherapy (p = 0.75). When chemotherapy was added to the mobilizing regimen, lengths of stay post autologous stem cell transplant increased but there was no statistically significant difference in length of stay between Neupogen® plus chemotherapy mobilization (median=22.0, IQR =20.0-26.0) versus Grastofil® plus chemotherapy (median=24.0 days, IQR =21.0-29.0) mobilization (p-value =0.10). In conclusion, when comparing the use of either a Neupogen® or Grastofil® based mobilization regimen in terms of stem cell harvest success, Plerixafor® use, more than one apheresis day required, time to engraftment, and length of stay in hospital, no significant difference was found indicating that both products, the reference agent and its biosimilar have similar efficacy. The use of such biosimilars can provide substantial cost savings to the health care system. Disclosures Elemary: Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document