Higher Total Nucleated Cell Dose Research Articles

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Impact of conditioning regimen on peripheral blood hematopoietic cell transplant.

AIMTo investigate infused hematopoietic cell doses and their interaction with conditioning regimen intensity +/- total body irradiation (TBI) on outcomes after peripheral blood hematopoietic cell transplant (PBHCT).METHODSOur retrospective cohort included 247 patients receiving a first, T-replete, human leukocyte antigen-matched allogeneic PBHCT and treated between 2001 and 2012. Correlations were calculated using the Pearson product-moment correlation coefficient. Overall survival and progression free survival curves were generated using the Kaplan-Meier method and compared using the log-rank test.RESULTSNeutrophil engraftment was significantly faster after reduced intensity TBI based conditioning [reduced intensity conditioning (RIC) + TBI] and > 4 × 106 CD34+ cells/kg infused. A higher total nucleated cell dose led to a higher incidence of grade II-IV acute graft-versus-host disease in the myeloablative + TBI regimen group (P = 0.03), but no significant difference in grade III-IV graft-versus-host disease. A higher total nucleated cell dose was also associated with increased incidence of moderate/severe chronic graft-versus-host disease, regardless of conditioning regimen. Overall and progression-free survival were significantly better in patients with a RIC + TBI regimen and total nucleated cell dose > 8 × 108/kg (3 years, overall survival: 70% vs 38%, P = 0.02, 3 years, progression free survival: 64% vs 38%, P = 0.02).CONCLUSIONTBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Immune cell subsets may predict improved survival after unmanipulated PBHCT.

Prognostic Effect of Bone Marrow (BM) and Peripheral Blood Stem Cell (PBSC) Donor Cell Subsets on Myeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes

Allogeneic HCT is a crucial tool for the treatment of hematologic malignancies, immune-deficiencies, and metabolic disorders. Donor-derived T-cells are critical for the graft-versus-leukemia effect, assist in engraftment, and protect against infections; however, they are also involved in the development of graft-versus-host-disease (GVHD). Although total nucleated cell (TNC) dose and CD34 cell doses have previously been correlated with post-transplant outcomes, there are limited data on the role of donor T-cell subsets in engraftment and post-HCT complications including GVHD. We examined the association of donor cell subset data with outcomes in myeloablative allogeneic HCT recipients from 2002 to 2014 in our single-center retrospective cohort study.Analysis was restricted to recipients of BM (N=359) or G-CSF mobilized PBSC (N=61) grafts from HLA-identical sibling and unrelated donors. Total nucleated cell (TNC), CD34, CD3, CD4, CD8, and CD56 (PBSC only) doses from the pre-infusion graft were analyzed for association with disease and outcome data prospectively collected by our institution’s HCT database. Multivariable Fine and Gray or Cox regression analyses adjusted for clinical variables and evaluated association of donor cell subset with the following outcomes: neutrophil engraftment (>500/uL x 3 days), platelet engraftment (>20,000/uL x 3 days), lymphocyte recovery (>500/uL x 1 day), any infection, donor chimerism (≥95% by day 100), grade 2-4 acute GVHD, chronic GVHD, non-relapse mortality (NRM) and overall survival. Analyses were performed separately for BM and PBSC groups.In the BM cohort, median recipient age was 47 years; 77% patients had acute leukemia/MDS; 58% had HLA-identical sibling donor. Most patients received ablative Bu-Cy (63%) or etoposide-TBI (19%) conditioning, with CNI-MMF (49%) or CNI-MTX (47%) as GVHD prophylaxis. Donor median age was 42 years and 39% were CMV positive. The mean graft (/kg) TNC and CD34 doses were 2.29x108 and 2.52x106, and mean T-cell subset doses were 32.19x108 CD3, 17.92x108 CD4, and 12.75x108 CD8, respectively. Among patients receiving a PBSC graft, median age was 48 years, 82% had acute leukemia/MDS, and 64% had an unrelated donor. Similar to BM, most patients received ablative Bu-Cy (67%) or etoposide-TBI (15%) conditioning, and CNI-MMF (33%) or CNI-MTX (61%) for GVHD prophylaxis. Median donor age was 40 years and 36% were CMV seropositive. The mean graft cell doses (/kg) were 9.51x108 TNC, 5.50x106 CD34, 2.74x108 CD3, 1.75x108 CD4, 0.88x108 CD8, and 0.36x108 CD56, respectively. Median time to neutrophil, lymphocyte and platelet recovery was 15, 27 and 23 days, respectively in the BM cohort, and 12, 19 and 16 days, respectively in the PBSC cohort. The table shows significant associations between donor cell subsets and post-HCT outcomes from the multivariable analysis.In summary, among myeloablative allogeneic HCT patients receiving BM grafts, earlier neutrophil engraftment was seen with higher TNC dose, while platelet engraftment and lymphocyte recovery was seen with higher CD34 dose. Among PBSC grafts, higher CD8 dose was associated with earlier lymphocyte recovery, higher CD4 dose with lower risk of infection, and higher CD34 dose with greater risk of acute GVHD but lower risk of NRM. The relative contribution of each donor cell subset between BM and PBSC grafts can impact outcomes. We did not observe any association of donor cell subsets with donor chimerism, chronic GVHD, or overall survival in this population. BM and PBSC graft composition can impact myeloablative allogeneic HCT outcomes and future studies to evaluate optimal graft composition are needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34+ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation.

Mobilized peripheral blood is the most common graft source for allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning. In assessing the effect of donor cell dose and graft composition on major transplant outcomes in the reduced-intensity setting, prior studies focused primarily on CD34(+)cell dose and reported conflicting results, especially in relation to survival end-points. While the impact of total nucleated cell dose has been less frequently evaluated, available studies suggest higher total nucleated cell dose is associated with improved survival outcomes in the reduced-intensity setting. In order to further explore the relationship between CD34(+)cell dose and total nucleated cell dose on reduced-intensity transplant outcomes, we analyzed the effect of donor graft dose and composition on outcomes of 705 patients with hematologic malignancies who underwent reduced-intensity peripheral blood stem cell transplantation at the Dana Farber Cancer Institute from 2000 to 2010. By multivariable analysis we found that higher total nucleated cell dose (top quartile; ≥10.8 × 10(10)cells) was associated with improved overall survival [HR 0.69 (0.54-0.88),P=0.0028] and progression-free survival [HR 0.68 (0.54-0.85),P=0.0006]. Higher total nucleated cell dose was independently associated with decreased relapse [HR 0.66 (0.51-0.85),P=0.0012] and increased incidence of chronic graft-versus-host disease [HR 1.4 (1.12-1.77),P=0.0032]. In contrast, higher doses of CD34(+)cells (top quartile; ≥10.9 × 10(6)/kg) had no significant effect on graft-versus-host disease or survival outcomes. These data suggest total nucleated cell dose is a more relevant prognostic variable for reduced-intensity transplant outcomes than the more commonly studied CD34(+)cell dose.

Association of higher total nucleated cell dose with improved survival in patients receiving donor lymphocyte infusion after allogeneic stem cell transplantation.

7028 Background: Donor lymphocyte infusion (DLI) after allogeneic stem cell transplant is an established therapy for disease relapse. Long-term survival after DLI remains poor, and identification o...

Higher Total Nucleated Cell Dose, but Not CD3+, 4+, 8+, or 34+ Cell Dose, Is Associated with Better Overall and Progression-Free Survival after Allogeneic Peripheral Blood Hematopoietic Cell Transplantation (AlloPBHCT) with TBI-Based Conditioning Regimens

Higher Total Nucleated Cell Dose, but Not CD3+, 4+, 8+, or 34+ Cell Dose, Is Associated with Better Overall and Progression-Free Survival after Allogeneic Peripheral Blood Hematopoietic Cell Transplantation (AlloPBHCT) with TBI-Based Conditioning Regimens

Impact Of Total Nucleated Cell and CD34+ Cell Dose On Transplant Related Outcomes In Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplants

BackgroundMobilized peripheral blood (PB) is the most common graft source for allogeneic hematopoietic transplantation (HCT) following reduced intensity conditioning (RIC). The impact, if any, of donor PB graft composition on major transplant outcomes in the RIC allogeneic HCT setting remains incompletely understood. Existing studies have focused primarily on CD34+ cell dose and report conflicting results, especially in relation to survival. The impact of total nucleated cell (TNC) dose has been less frequently evaluated, but limited studies with relatively small cohort sizes have reported higher TNC dose to be associated with improved survival. MethodsIn order to further explore the relationship between PB donor CD34+ cell dose, TNC dose and RIC HCT outcomes, we assessed 705 adult patients with hematological malignancies who underwent RIC allogeneic HCT at Dana Farber Cancer Institute/ Brigham and Women's Hospital (DFCI/BWH) between 2000 and 2010. The vast majority received a RIC regimen of fludarabine and busulfan (n=698). GVHD prophylaxis was tacrolimus based with or without sirolimus (524 vs. 171, respectively). Recipients of in vivo T-cell depletion (TCD) with antithymocyte globulin or ex-vivo TCD were excluded. The median age was 57 years (range,18-74). Patient's disease risk index (DRI) was categorized as low (n=164), intermediate (n=350), high (n=170) or very high (n=21) per Armand, et al (Blood, 2012). Transplants were categorized as matched (MRD n=273, MUD n=374) or mismatched (MMRD n=4, MMUD n=58). ResultsThere was weak correlation between CD34+ cell dose and TNC (Spearman coefficient 0.25 [0.18-0.32]), and between CD34+/kg and TNC/kg with coefficient 0.25 [0.26, 0.39]. Cell doses for TNC effects were evaluated by quartiles. On multivariable analysis including age, DRI, donor source, gender, and CMV serostatus, higher TNC dose (top quartile, ≥10.8 x 10^10 cells) was independently associated with increased chronic GVHD (HR 1.33 [1.06-1.67], p=0.015) as well as decreased relapse (HR 0.74 [0.58-0.94], p=0.015). There was no effect on acute GVHD, engraftment, or non-relapse mortality. Importantly, higher TNC dose was associated with improved overall survival (HR 0.74 [0.59-0.94], p=0.014, Figure 1) and progression free survival, PFS (HR 0.76 [0.61-0.94], p=0.014). In contrast, although higher doses of CD34+ cells (> 10 x 10^6/kg vs. < 5 x10^6/kg) resulted in faster engraftment for both platelets and neutrophils (data not shown) and a decrease in non-relapse mortality ( HR 0.53 [0.30-0.93], p=0.027), there was no significant effect on acute or chronic GVHD incidence, relapse, PFS or survival. [Display omitted] ConclusionsThese data suggest TNC dose is an important prognostic variable in T-replete RIC HCT with significant impact on survival and should, like CD34+ cell dose, be taken into consideration when planning donor graft infusions. Further studies are needed to confirm these data, and characterize the components of the PB graft that influence survival. Disclosures:No relevant conflicts of interest to declare.

Reduced-intensity conditioned allogeneic haematopoietic stem cell transplantation results in durable disease-free and overall survival in patients with poor prognosis myeloid and lymphoid malignancies: eighty-month follow-up

The long-term outcome of patients with haematological malignancies treated with reduced-intensity conditioned allogeneic peripheral blood stem cell transplantation is not known. We report the outcome of 79 patients with poor-risk myeloid and lymphoid malignancies transplanted with reduced-intensity conditioning (RIC) regimens. The diagnoses include AML/myelodysplastic syndrome (n=43), non Hodgkin's lymphoma (n=30), Hodgkin's lymphoma (n=3), ALL (n=2) and CML (n=1). For the entire cohort, the disease-free survival (DFS) and OS were 61.2 and 35.7%, respectively. Twenty patients relapsed, 18 within the first three years, and 14 patients succumbed to progressive disease. Overall, 31 patients died from transplant-related complications within the first three years. Day 100 non-relapse mortality correlated with a higher total nucleated cell dose in the graft (odds ratio: 3.9). For those in CR at 3 years, the DFS and OS were 84.2 and 81.1%, respectively. Furthermore, of 43 patients with active disease at the time of transplantation, 16 remained in CR after 3 years. The majority of the long-term survivors were functioning independently. One patient died from a second malignancy. No post-transplant lymphoproliferative disorder was seen. In conclusion, durable disease control was achieved after RIC allogeneic stem cell transplantation for patients with advanced myeloid and lymphoid malignancies.

Cord blood transplant in childhood ALL

Optimal therapy for high risk and relapsed acute lymphoblastic leukemia (ALL) remains uncertain. Wider availability of cord blood from related and unrelated donors has prompted studies of its use for hematopoietic stem cell transplant (HSCT). We evaluated 26 consecutive cord blood transplants (CBT) for ALL performed at our center from 1996 to 2002 on studies using consistent conditioning therapy and graft-versus-host disease (GVHD) prophylaxis. Median patient age was 8.5 years (range, 0.5-24 year). Cord blood (CB) was from unrelated donors in 25/26 cases. Median CB nucleated cell dose was 3.26e7/kg (range, 0.8-12.9). With median follow-up of 548 days, 16/26 patients (62%) are event-free survivors. Acute GVHD developed in 14/24 evaluable patients, reaching grade III-IV in 7 patients. Chronic GVHD occurred in 10/22 evaluable patients. Multivariate analysis showed higher total nucleated cell dose per kilogram to be the strongest predictor of event-free survival. We conclude that CBT can effectively treat ALL in children with high risk features and following relapse.