Comparison of Immune Reconstitution after Umbilical Cord Blood (UCB) and Allogenic Peripheral Blood Stem Cell (APBSC) Transplantation in Patients with Advanced Multiple Myeloma (MM) and Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5008-5008
Author(s):  
Jean-Come Meniane ◽  
Patrice Ceballos ◽  
Maud Condomines ◽  
Jean-françois Eliaou ◽  
Nathalie Fegueux ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Tumor Control ◽  
High Dose ◽  
Cell Recovery ◽  
Significant Difference ◽  
Cd8 Cell

Abstract Background. T-cell reconstitution is usually delayed after UCB transplantation, in addition to an impaired thymopoiesis and late memory T cell skewing. NK cells are usually variable, with an initial increase in % and absolute number. The role of these cells is unclear, particularly on tumor control, maybe participating to the T-cell lymphopenia. Patients and methods. F rom 01/03 to 04/07, we retrospectively analysed data concerning lymphocyte recovery for patients having MM and AML, who received allogenic transplantation (AT). We excluded patients with progressive disease before AT, with short follow-up (<120days) and without dominant donor chimerism. 43 patients (MM, n=19; AML, n=24) were included, and they received UCBT (n=13: MM=7 and AML=6; single: n=2 or double: n=11), all with reduced intensity conditioning (RIC) regimen adapted from the Minneapolis protocol, or APBSC (n=30) [RIC (n=23; MM=12 and AML=11), including ATG (n=12/23; AML=10/11) or myelo-ablative conditioning (MAC: n=7, all having AML,]. Immune reconstitution in PB was followed, including CD3+, CD4+, CD8+, CD3−/CD56+, and CD19+ cells, monthly. Prophylaxis of GVHD included cyclosporin A from d-3 to months +3 or +6, according to clinical manifestations of GVHD, and mycophenolate mofetil from d-3 to d+28 after RIC regimen and standard prophylaxis with cyclosporine and short course methotrexate after MAC regimen. Anti-infectious prophylaxis and follow-up were standard. Results. Median age was comparable between groups (MM: DUCB (57y, 42–61), PBSC (55y, 50–68); AML: DUCB (45y, 30–63), PBSC (53y, 21–64). Sex ratio (F/M) was 6/13 for MM, and 11/13 for AML. In the group MM/UCB, NK cells was above 80/mm3 from D-7 to 1 year and peaked at D260 (median=193/mm3), with no statistical difference with the MM/PBSC group (64 at D-7 to 132/mm3). NK cells were significantly higher (p=0.04) for AML/UBC group (from D90: 187/mm3) to D260: 328/mm3), in comparison to AML/PBSC (from 116 to 138/mm3). For CD4 T-lymphocytes, there was a significant difference between MM/UCB and MM/PBSC during the first 3 months [39 to 75/mm3 vs 152 to 175/mm3, p=0.01]. A more rapid recovery of CD4+ was observed in AML/UBC (from 227 to 829/mm3, D90 to 1y), 2-fold higher than in the AML/PBSC at any time. Those differences could be explained by the high-dose therapy given to patients with MM. In addition, patients who received ATG (all AML/PBSC/RIC) had a delayed CD4 recovery. CD8-cell recovery was delayed for UBC groups with a CD8 cell count >200 starting at D230 as compared to the PBSC group (D150 for MM and D90 for AML). B cell recovery was faster in the UCB group [MM/UCB and AML/UCB, >200/mm3 at D230 and D150 as compared to D300 and D230 respectively in MM/PBSC and AML/PBSC (p=NS)]. Conclusion. NK cells increased after UBC more intensively and rapidly than after PBSC AT. T-cell recovery appeared to be associated to pre-treatment intensity and use of ATG. CD4, CD8 counts were highly reduced in UCB compared to PBSC except for CD4+ in AML/UCB. B-cell recovery is not different between both groups (i.e. UCB and PBSC). NK cells from 2 patients are now collected for analysis of their functions particularly their anti-tumoral effect in vitro.

Improved Outcomes of Autologous (Auto) Hematopoeitic Stem Cell Transplantation (HSCT) for Intermediate and High Risk (I/HR) Aggressive (AG) Non Hodgkin Lymphoma (NHL) with IV vs PO Busulfan (Bu) in a Bu, Cyclophosphamide (Cy) and Etoposide (E) Preparative Regimen.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1881-1881
Author(s):  
Charu Aggarwal ◽  
Sameer Gupta ◽  
Donna E. Salzman ◽  
Amy G. Dickey ◽  
William P. Vaughan
Keyword(s):  
T Cell ◽  
B Cell ◽  
Progression Free Survival ◽  
High Dose ◽  
Time Curve ◽  
Significant Difference ◽  
Mantle Cell ◽  
Preparative Regimen ◽  
Large B Cell

Abstract The BUCYE preparative regimen was originally developed for allogeneic HSCT for advanced hematological malignancy (BMT 4:489-495). We have been using it as high dose chemotherapy for auto-HSCT for malignant lymphoma patients (pt). We have now had the opportunity to review the results of this experience in 49 I/HR AG NHL pt transplanted between 8/94 and 9/03. Eighteen pt treated before 4/99 received CY 2.5 Gm/M2/d d −3 to −1 and E 1800 mg/M2 over 4 hr on d −3 following BU 1mg/Kg Q6h X 16 doses administered po beginning on d −7. Since 4/99, 31 pt have received the same regimen substituting iv BU using Pharmacokinetics (PK) guided dosing to target an area under the concentration*time curve (AUC) of 1000–1400μMol *min on the same Q6h X 16 dose schedule. Eleven of these pt, treated prior to 3/01, had dose 8 adjusted based on dose1 PK and the remaining 20 had dose 1 or 2 adjusted based upon a test dose. We hypothesized that reduced inter- and intra-pt variation in AUC due to PK guided iv BU would reduce the risk of over or under treatment with excess risk of toxicity or relapse as compared to po administered drug. The age range (18–69, med 53 for po pt; 19–68, med 51 for iv pt), HR ratio (7/18, 39% for po pt; 14/31, 45% for iv pt), and number of prior chemotherapy regimens (1–3, med 2 for both) were the same for both the iv and po groups. The distribution of histological sub-classifications was also not different. The iv group consisted of 23 Diffuse Large B-Cell, 1 Burkitt, 2 Mantle Cell, 2 T cell and 3 others. The po group contained 16 Diffuse Large B-Cell, 2 Mantle Cell, 1 T cell and 4 others. The non-relapse mortality for the po BU pt was 5/13 (28%) and for the iv BU pt was 1/31 (3%) (p = 0.01 chi square). The overall survival (OS) for the po pt is currently 28% with no deaths beyond 4 yr and med follow up of survivors of 7 yr (range 4–10); in contrast the OS is 63% for the iv pt with no deaths beyond 2 yr and median follow up of survivors of 2 yr (range 4 mo to 4.5 yr), (p = 0.012 log rank). The progression free survival (PFS) is 22% for the po pt and 55% for the iv pt (p = 0.013 log rank). During the same time period we treated 48 Hodgkin’s disease (HD) pt with the same regimen (17 po, 31 iv). There was no significant difference in any outcome parameter between iv and po regimens in this significantly younger (19–63 yr, med 31) and otherwise lower risk population. With follow up of survivors from 18 to 90 mo (med 36), OS is 60% at median follow up and PFS is 50%. Overall, the results of the use of the BUCYE regimen in auto HSCT for both HD and NHL are excellent. The substitution of PK guided iv BU for the more erratic po administration in the BUCYE regimen appeared to be responsible for reduced relapse rate and non-relapse mortality with improved OS and PFS. These results are especially dramatic in the I/HR AG NHL pt, the group at highest risk for relapse and regimen related mortality.

scholarly journals Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Elena Blanco ◽  
Natalia Izotova ◽  
Claire Booth ◽  
Adrian James Thrasher
Keyword(s):  
Gene Therapy ◽  
T Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Cell Recovery ◽  
Hematopoietic Stem ◽  
Conditioning Treatment ◽  
Immunodeficiency Disease

X-linked severe immunodeficiency disease (SCID-X1) is an inherited, rare, and life-threating disease. The genetic origin is a defect in the interleukin 2 receptor γ chain (IL2RG) gene and patients are classically characterized by absence of T and NK cells, as well as presence of partially-functional B cells. Without any treatment the disease is usually lethal during the first year of life. The treatment of choice for these patients is hematopoietic stem cell transplantation, with an excellent survival rate (&gt;90%) if an HLA-matched sibling donor is available. However, when alternative donors are used, the success and survival rates are often lower. Gene therapy has been developed as an alternative treatment initially using γ-retroviral vectors to correct the defective γ chain in the absence of pre-conditioning treatment. The results were highly promising in SCID-X1 infants, showing long-term T-cell recovery and clinical benefit, although NK and B cell recovery was less robust. However, some infants developed T-cell acute lymphoblastic leukemia after the gene therapy, due to vector-mediated insertional mutagenesis. Consequently, considerable efforts have been made to develop safer vectors. The most recent clinical trials using lentiviral vectors together with a low-dose pre-conditioning regimen have demonstrated excellent sustained T cell recovery, but also B and NK cells, in both children and adults. This review provides an overview about the different gene therapy approaches used over the last 20 years to treat SCID-X1 patients, particularly focusing on lymphoid immune reconstitution, as well as the developments that have improved the process and outcomes.

Natural Killer Cell Immune Reconstitution Predicts Outcomes for Patients with Chronic Lymphocytic Leukemia Undergoing Allogeneic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3300-3300
Author(s):  
Don Benson ◽  
Leslie Andritsos ◽  
Mehdi Hamadani ◽  
Thomas Lin ◽  
Joseph Flynn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Immune Reconstitution ◽  
Nk Cell ◽  
Disease Status ◽  
Lymphocytic Leukemia ◽  
T Cell Subsets ◽  
Cell Recovery

Abstract Introduction: Chronic lymphocytic leukemia (CLL), the most common form of leukemia in the Western hemisphere, is associated with severe innate, adaptive and humoral immune dysregulation. CLL remains essentially incurable, with the potential exception of allogeneic stem cell transplantation (ASCT). Natural killer (NK) cells are CD56(+), CD3(−) large granular lymphocytes that comprise a key cellular subset of the innate immune system. Preliminary in vitro data suggest an NK cell versus CLL effect exists, similar to that observed in acute myeloid leukemia (AML) and other blood cancers. Novel immune therapies for CLL (e.g., rituximab, alemtuzumab) likely exert anti-tumor effect, in part, through NK cells, in fact. Although NK cells contribute to the graft-versus-tumor effect following ASCT for other blood cancers, little is known regarding the potential role NK cells may play in the clinical allogeneic transplant setting for CLL. Herein, we provide, to our knowledge, the first report regarding NK cell immune reconstitution following ASCT for CLL. Methods: 27 CLL patients underwent reduced intensity conditioning (RIC) with ASCT. Median age was 52 years (43–69), median number of prior therapies was 3 (2–11). 55% had chemotherapy-refractory disease, and 55% had “high-risk” cytogenetics by FISH (deletion 17p or 11q22-23 abnormality). 14 patients had sibling donors, 15 had volunteerunrelated donors. Conditioning regimens included Fludarabine/TBI/Alemtuzumab (n=8), Fludarabine/Busulfan with (n=9) or without ATG (n=6), and Fludarabine/Cyclophosphamide (n=4). GVHD prophylaxis consisted of tacrolimus/MMF (n=8) or tacrolimus/methotrexate (n=19). Patients underwent bone marrow assessment prior to day +75 following ASCT. Marrow was studied for engraftment, donor chimerism, and disease status as well as lymphoid immune reconstitution by percentage of total lymphocytes and absolute lymphocyte counts by multi-color flow cytometry. Results: NK cell immune reconstitution was predicted by disease status at transplantation. Patients in complete or partial remission at the time of ASCT had more robust NK cell recovery (mean = 45% of total lymphocytes +/− SEM 5%) as compared to patients entering transplant with refractory disease (16% +/− 1, p < 0.01). No differences were observed in CD4(+) or CD8(+) T cells and no lymphocyte subset recovery was associated with CD34(+) or CD3(+) cell dosage. Achieving complete donor chimerism by day +60 was associated with robust NK cell recovery (55% +/− 1 versus 7% +/−1, p = 0.02), recovery of CD4 and CD8 T cells was not associated with chimerism status, however. Patients who went onto exhibit a complete response to ASCT had greater early NK cell reconstitution (31% +/− 3) as compared to those who had no response (8% +/− 1, p = 0.01). No differences in T cell subsets were associated with response. Patients who ultimately achieved complete remission following transplant had a lower CLL:NK cell ratio in marrow (0.35 +/− 0.07) than those who did not (8.1 +/− 1, p = 0.01). However, differences in CLL:CD4(+) and CLL:CD8(+) T cells were not predictive of response. Trends to improvement in progression free survival and overall survival were observed for patients with NK cell reconstitution above the median for the group as compared to those below; no such trends were observed regarding T cell subsets. Greater NK cell reconstitution trended towards ultimate eradication of minimal residual disease following ASCT, but no such trends were observed for T cell subsets. Conclusions: Early NK cell recovery predicts survival following autologous and allogeneic SCT in a number of hematologic malignancies; however, little is known regarding this phenomenon in CLL. To our knowledge, these are the first findings to implicate a potentially important therapeutic role for early NK cell compartment recovery in CLL following ASCT. Further research into restoring and augmenting NK cell function following RIC/ASCT for CLL is warranted.

scholarly journals Haplo-Cord Transplantation with Anti-Thymocyte Globulin: Comparative Clinical Outcomes with or without Routine G-CSF Administration

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2000-2000
Author(s):  
Nina Orfali ◽  
Alexandra Gomez-Arteaga ◽  
Danielle Guarneri ◽  
Jingmei Hsu ◽  
Adrienne A. Phillips ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphocyte Count ◽  
Graft Failure ◽  
Immune Reconstitution ◽  
Univariate Analysis ◽  
Transplant Recipients ◽  
Platelet Recovery ◽  
Significant Difference ◽  
Neutrophil Engraftment

Introduction: Haplo-cord transplantation - the co-infusion of a single umbilical cord graft with CD34-selected cells from a haplo-identical donor, offers an alternative stem cell source for patients lacking HLA-matched donors. The T-cell depleted haplo-graft acts as a myeloid bridge until replaced by durable cord hematopoiesis. Anti-thymocyte globulin (ATG) is routinely used in haplo-cord preparative regimens to reduce graft failure, graft vs. host disease (GVHD) and graft vs. graft reactions. ATG depletes T-lymphocytes through Fas-mediated apoptosis, but also indirectly stimulates T-cell destruction through antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) (de Koning, Blood Adv. 2018). Excessive depletion of cord lymphocytes may compromise immune reconstitution and graft vs. tumor effects. G-CSF administration early post-transplant may sensitize cord lymphocytes to the cytotoxic effects of residual ATG. G-CSF drives myeloid precursor proliferation and activates phagocytosis, facilitating increased ADCP and ADCC of ATG-coated cells (de Koning, Blood Adv, 2018). Prior to the publication of this data, our institutional practice was to administer G-CSF to haplo-cord transplant recipients from day +6 until neutrophil engraftment. In April 2018, we altered our practice - withholding routine G-CSF treatment. We here compare our transplant outcomes 1 year before and after this practice shift. Methods: We examined consecutive adult patients with hematologic malignancy that underwent haplo-cord transplantation conditioned with fludarabine and melphalan with or without total body irradiation (400 cGy) at Weill Cornell Medicine, between 04/2017 and 04/2019. All patients received rabbit ATG (Thymoglobulin) 1.5 mg/kg on days -5, -3 and -1 (total dose 4.5 mg/kg). Data was collected as part of study 01810588 registered at clinicaltrials.gov. Probabilities of relapse, relapse-related mortality (RRM) and non-relapse mortality (NRM) were generated using cumulative incidence (CI) estimates to accommodate competing risks. Probabilities of overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier estimates and inter-group comparison performed by log-rank testing. Variables with potential survival impact were evaluated in a Cox proportional hazards regression model. Results: The study included 59 haplo-cord recipients - 30 who received G-CSF (GCSF group) and 29 who did not (NO GCSF group). Groups were well matched for age, weight, disease, DRI, baseline lymphocyte count, CMV recipient/donor status and TBI treatment (Table). Neutrophil engraftment occurred at a median of 10 days in the GCSF group vs. 14 days in the NO GCSF group (p=0.0002), and platelet recovery at a median of 20 and 22 days (p=-0.61). Primary graft failure occurred in 1 GCSF patient and 2 NO GCSF patients (p=0.53). The incidence of acute GVHD (grade II-IV) by day 100 was 10% in both groups (p=0.97). There was no significant difference between GCSF and NO GCSF in the CIs of relapse, RRM or NRM at 1yr. No difference was found in 1yr OS or PFS on univariate analysis (Table). After adjusting for patient age, weight, lymphocyte count prior to ATG, disease subtype, CIBMTR disease risk index (DRI), Karnofsky performance status (KPS), comorbidity score and TBI exposure, in multivariate analysis, no effect on OS or PFS was observed. CMV reactivation was observed in 40% (GCSF) vs. 21% (NO GCSF) (p=0.11). The trend towards lower reactivations in the NO GCSF may in part be due to the introduction of letermovir prophylaxis for CMV positive transplant recipients in 02/2018. Acknowledging the limited follow up of NO GCSF patients, we note a trend towards improved CD4 counts at 1yr in this group - median 271 cells/μL (n=6, IQR25-75 = 240-342) vs. 155 cells/μL in the GCSF group (n=16, IQR25-75 = 111-473) (p=0.17). Conclusion: Our data shows that G-CSF can safely be eliminated from haplo-cord transplant. We see a delay in neutrophil engraftment but no adverse effect on early morbidity or mortality outcomes. We continue to withhold early G-CSF while assessing long-term outcomes. Longer follow-up is needed in our cohort to enable a systematic analysis of immune reconstitution. Early CD4+ cell recovery after ATG treatment has been shown to improve OS, PFS, NRM and RRM (Admiraal, Lancet Hem 2015 & 2017). Disclosures Van Besien: Miltenyi Biotec: Research Funding.

scholarly journals Comparison of Fixed Vs ALC-Based Doses of Thymoglobulin® (ATG) in Pediatric Patients with Acute Leukemia Given αβhaplo-HSCT: Impact on Immune Reconstitution at Day 90

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-16
Author(s):  
Giulia Barbarito ◽  
David C Shyr ◽  
Gopin Saini ◽  
Linda Oppizzi ◽  
Y. Lucy Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Pediatric Patients ◽  
Conditioning Regimen ◽  
Optimal Dose ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Αβ T Cells

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for pediatric patients with high risk or refractory leukemia. In the absence of related or unrelated HLA-matched donors, alternative approaches such as HLA-haploidentical HSCT have been implemented. Our group has developed one such approach, αβ T-cell/CD19 B-cell depletion (αβhaplo-HSCT), and demonstrated its clinical efficacy (Bertaina A, Blood 2018). In αβhaplo-HSCT, anti-thymocyte globulin (ATG) is used for preventing graft rejection and graft-versus-host disease (GvHD). However, the optimal dose still needs to be elucidated. Here, we present the first analysis comparing 2 different Thymoglobulin® ATG doses: one fixed at 3.75 mg/Kg, as established in previous European studies with the closely related ATG Grafalon®, and one based on a newly developed algorithm that also integrates absolute lymphocyte count (ALC). METHODS: Between March 2017 and April 2020, 27 pediatric patients (median age 12 years) with hematological malignancies were transplanted at Stanford University's Lucile Packard Children's Hospital. Importantly, 60% of these patients were in CR2 or greater and 2/27 had active disease at the time of HSCT. All children received a fully myeloablative conditioning regimen. On days -9/-8/-7 before αβhaplo-HSCT, patients were given a regimen of Thymoglobulin® ATG. No patient received post-HSCT pharmacological GvHD prophylaxis. The fixed dosage was given to 14 patients in cohort 1 (ATG: 3.75 mg/Kg) and the novel ALC-based dosage to 13 in cohort 2 (ATG ranging between 3-6 mg/Kg). All patients enrolled in this study (BMT Protocol 179 and 351 approved from our IRB) had a minimum follow-up of 100 days, evaluated at Day 30 and 90. Following Admiraal R (Lancet Hematology 2015), we defined CD4 immune reconstitution (IR) as more than 50 CD4 T-cells/ul twice within the first 100 days after HSCT. PBMC were enriched by Ficoll-Hypaque (Sigma Aldrich) density gradient centrifugation. Flow analyses were performed on fresh cells resuspended in PBS 2% FBS on Cytek DxP 10 flow-cytometer. At least 5x104 events of total cells were acquired and analyzed using FloJo software. RESULTS: With a median follow-up of 555 and 124 days for cohort 1 and 2 respectively, 12 patients (85.7%) in cohort 1 and 7 patients (54%) in cohort 2 achieved CD4 immune reconstitution. In cohort 2, CD3 αβ T cells were significantly lower at both Day 30 and Day 90 (P=0.0003, Figure 1A). At Day 90, both the CD4 and CD8 subpopulations were significantly depressed (P=0.01 and P=0.056, respectively, Figure 1C). In both subpopulations, the memory compartment was the most reduced (Figure 1D). The absolute numbers of CD3 γδ T cells did not differ between the cohorts at either Day 30 or 90 (Figure 1B). Viral reactivations were higher in cohort 1 (10/14, 71%) than in cohort 2 (6/13, 46%, P=NS). Half of the reactivations were CMV reactivations, but no patient developed organ disease. There was no statistically significant difference in overall survival and the incidence of relapse in the two cohorts. Three patients developed grade III-IV aGvHD: 2 in cohort 1 (14%) and 1 in cohort 2 (8%, P=NS). Remarkably, the only patient, who developed grade IV aGvHD in cohort 2, did not experience symptoms until Adenovirus reactivation 138 days after HSCT. CONCLUSION: Our analysis confirms that the optimal dose of ATG Thymoglobulin® before αβhaplo-HSCT remains elusive. There were no significant clinical differences between the 2 ATG regimens. However, the ALC-based regimen resulted in the more pronounced reduction of donor-derived memory T cells. Our analysis suggests two intriguing explanations for the observed pattern of results. First, the selective depletion of the memory compartment in both CD4 and CD8 T cells may well be due to a priming effect of ATG Thymoglobulin® on the few αβ T cells left over in the graft. Second, the equivalent reconstitution of naive T cells in the 2 cohorts is likely because the ATG has no impact on the thymus-dependent IR. Remarkably, in our overall cohort, 70% of the patients achieved CD4 IR by 90 days after αβhaplo-HSCT. This result is superior to the best results from other ex vivo T-cell depleted approaches 54%, recently reported by Van Roessel (Cytotherapy 2020). In vivo studies of the pharmacokinetics of ATG in αβhaplo-HSCT recipients and a comparison with the use of Grafalon® are required to shed more light on this crucial topic. Disclosures No relevant conflicts of interest to declare.

scholarly journals Functional B Cell Reconstitution Following Allogeneic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-40
Author(s):  
Thuy N. Ho ◽  
Maheen Khan ◽  
Bennett Clark ◽  
Elizabeth Krieger ◽  
Catherine H Roberts ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Immune Recovery ◽  
Cell Recovery ◽  
Post Transplant ◽  
Cell Counts ◽  
Th Cell ◽  
Significant Difference ◽  
Antibody Titers

Immune reconstitution is critical to long term survivability in recipients of allogeneic hematopoietic cell transplantation (HCT), mitigating both relapse as well as infection risk. However, both graft versus host disease (GVHD) and post HCT immunosuppression used to prevent it impair immune recovery, particularly functional B cell reconstitution which may not happen for several months post-transplant. This is relevant for post-transplant vaccination which in some centers is delayed till immune cell recovery. In this retrospective, Virginia Commonwealth University institutional review board (IRB) approved study, T helper and B cell recovery for up to two years following HCT was evaluated in 212 patients transplanted between 2015 and 2019. There were 69 HLA matched related & 143 unrelated donor transplant recipients. Median age of the patients was 56 years (range 19-74); conditioning regimens utilized were reduced intensity (RIC) in ~62% of the patients and rabbit anti-thymocyte globulin was used in ~72% of the patients. Blood stem cells were given in 183 patients and bone marrow in 29. Only patients with hematological malignancies were included in this study. Landmark analysis was carried out, with patients who did not survive the first 6 months post-transplant excluded. Of these patients, 85% are surviving. Median CD3+/4+ (Th) cell counts were 153 at 6 months, 228 at 1-year, 296 at 2 years, and corresponding B cell counts were 70, 175, & 273. Plotting Th and B cell counts over time in each individual donor-recipient pair demonstrated close correspondence between Th and B cell recovery, with synchronous recovery observed in most patients, median R 0.76 (range: 0.01-0.99). The slope of the B/Th cell curves for each patient then were compared in a subset of patients, and demonstrated a significant difference between those patients who either did not develop GVHD or only had acute GVHD as opposed to those who developed both acute and chronic GVHD (1.3±1.4 B cells/Th cells and 1.1±1.2 vs. 0.5±1, P=0.02 and 0.06 respectively), suggesting poor B cell recovery in those with chronic GVHD. Different immune recovery kinetics were observed amongst patients (Figure 1); A) rapid B cell recovery, highest absolute B cell count between 30 and 180 days post-HCT, B) intermediate B cell recovery, days 180 and 455, C) delayed B cell recovery, days 455 and 725 days, and D) minimal to no B cell recovery. A higher relative risk for developing acute + chronic GVHD was seen in the intermediate B cell recovery group when compared to those with delayed recovery, RR = 2.38 (95% CI 1.08-5.25). Functional B cell studies were performed in a subset, by measuring IgG levels and anti-pneumococcal antibody titers. Correlation was observed between Th cell count and IgG levels over time in individual patients (median R = 0.57). Pneumococcal titers were also measured at approximately 6 months, 1- and 2-years post-transplant as patients were given a series of PCV13 & PSV23 vaccinations 6 months after HCT. When the antibody titers against unique pneumococcal serotypes were analyzed in individual patients, these varied within each individual, following a declining trend in levels for antibodies against different serotypes; this decline occurred on a logarithmic scale suggesting differential immunogenicity of the pneumococcal antigens, and also mathematically ordered, rather than random Th and B cell responses (Figure 2A). When the serotypes with the highest titers in most patients were correlated with Th and B cell counts measured simultaneously, no association was observed. Further, when fold increase in pneumococcal titers beyond 1-year post transplant were compared across different groups of patients based on their GVHD status, no significant difference was observed in their antibody responses (Figure 2B). In conclusion, our data suggest synchronous Th and B cell reconstitution post allogeneic HCT, both in numeric and functional terms, and thus strategies to help promote T cell recovery, such as IL-7 administration post-transplant, are necessary to encourage optimal immune reconstitution. Vaccine responses beyond 6 months, as in the institutional practice reported here, are independent of GVHD status and numeric immune cellular recovery. These findings are consistent with the notion that immune recovery is a dynamical, rather than a stochastic process. Disclosures No relevant conflicts of interest to declare.

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