Allogeneic Peripheral Blood Hematopoietic Cell Research Articles

Association of CD34+ Cell Dose with Progression-free Survival after Allogeneic Peripheral Blood Hematopoietic Cell Transplantation in Children with Hematologic Malignancies

A higher CD34+ cell dose is associated with improved engraftment but may also be associated with an increased risk of complications after allogeneic hematopoietic stem cell transplantation, including graft-versus-host disease (GVHD). We retrospectively analyze the impact of CD34+ cell dose on OS, PFS, neutrophil engraftment, platelet engraftment, treatment-related mortality, and GVHD grading. For analyses, CD34+ cell dose was stratified into low (< 8.5×106/kg) and high (> 8.5×106/kg). A subgroup analysis of higher CD34+ cell dose leads to prolonged OS and PFS, but statistical significance was achieved only for PFS (OR 0.36; 95%CI 0.14-0.95; P=0.04). This study reinforced that CD34+ cell dose at the time of allo-HSCT retained a positive impact on PFS.

Phase I Study of Baricitinib Gvhd Prophylaxis in HLA-Matched, Peripheral Blood Allogeneic Hematopoietic Cell Transplant

Acute graft versus host disease (aGVHD) is a leading cause of non-relapse mortality after allogeneic peripheral blood hematopoietic cell transplant (PB-HCT). JAK inhibition has been shown to be an effective treatment for steroid refractory aGVHD. We performed a single arm, open label, phase I trial to evaluate the safety of a best-in-class balanced JAK1/2 inhibitor, baricitinib (Bari), for the prevention of aGVHD after HLA-matched, allogeneic PB-HCT (Choi et al. Leukemia2018; Kim et al. Leukemia, 2022). The study enrolled 24 subjects into two dosing cohorts (2mg and 4mg daily) from 2019 - 2022. The data cut-off for this analysis was June 1, 2022. The primary objectives were to determine the incidence of graft failure at 28 days post HCT and the cumulative incidence of grade III-IV acute GVHD by day 100. The secondary objective was to determine day 180 treatment related mortality. Subjects were treated with Bari 2mg or 4mg (n = 12/cohort) oral daily from days -3 to +100, followed by a taper. All subjects received standard of care GVHD prophylaxis with tacrolimus and mini-methotrexate +/- thymoglobulin (n=19) or post-transplant cyclophosphamide (pTCy) plus mycophenolate mofetil and tacrolimus (n=5). At data cut, the median follow up was 320 days (63-368 days). The median age was 57 (range 28-72), and diagnoses included AML (16), MDS (6), and ALL (2). All subjects with AML were required to be in CR/CRi and 8 were MRD positive by flow cytometry at the time of transplant. Ten recipients had PB-HCT from sibling donors and 14 had PB-HCT matched unrelated donors. Conditioning included myeloablative regimens (MAC, n=19) or reduced intensity (RIC, n=5). GVHD prophylaxis included tacrolimus /methotrexate for all subjects in the 2mg cohort and pTCy was used in 5 / 12 subjects in 4mg dosing cohort. Thymoglobulin was allowed for MUD recipients (n=5). No events of primary graft failure were observed. The median ANC engraftment was 12.5 days (range 12-21). The median platelet engraftment was 20 days (range 13-52). Treatment related mortality at day 180 was 8% (2/24). The cumulative incidence of grade III/IV aGVHD at day 100 was 4% (1/24, occurring in the 4mg cohort), while the overall incidence of grade III/IV aGVHD at any time was 12.5% (3/24) and two of these cases occurred after Bari discontinuation. The one case of grade III aGVHD prior to day 100 was a steroid-responsive lower GI GVHD that occurred at day 21 in the 4mg cohort and did not recur with taper of immune suppression and Bari. Grade II - IV aGVHD occurred in 33% (8/24, 4 in the 2mg cohort and 4 in the 4mg cohort). Two cases were steroid refractory (one in 2mg and one in 4mg cohorts). All cases of grade II aGVHD were responsive to steroids. We found no association between GVHD prophylaxis backbone regimen and incidence of aGVHD. 11 cases of chronic GVHD (3 mild and 8 moderate severity) have been reported. Of the moderate cGVHD cases, 4 developed in the 2mg cohort and 4 in the 4mg cohort. No unexpected grade 3/4 adverse events (AE) were observed. Thromboembolic disease was an AE of special interest. Four DVTs were observed: 1 in the 2mg cohort vs. 3 in 4mg cohort. All subjects in the 4mg cohort had pulmonary embolism occurring while off Bari, one occurring at 10 months post-transplant, one at day 141 and another at day 152. Of the evaluable cases at day 100, 14/15 (93%) receiving MAC vs. 4/5 (80%) receiving RIC conditioning achieved >95% bone marrow donor engraftment, whereas, 11/16 (69%) receiving MAC vs. 4/4 (100%) receiving RIC had mixed peripheral blood CD3 T-cell chimerism. Of those with mixed CD3 chimerism at day 100, 12 remain in remission and 3 have relapsed. The incidence of disease relapse at 1 year was 21%, with 2 relapses occurring in the 2mg cohort and 3 in the 4mg cohort. Of the 8 cases with MRD positivity at transplant, 2 relapsed within 3 months of transplant and both had AML. The 1-year overall survival was 70%. The one-year refined GVHD relapse free survival (GRFS) was 33%. In conclusion, Baricitinib is safe after HLA-matched, allogeneic PB-HCT with no episodes of primary graft failure and low rates of grade III/IV acute GVHD while on therapy. A follow up efficacy study to evaluate extended duration of the 2mg dose of Bari focused on AML patients receiving HLA matched transplants and myeloablative conditioning is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chronic Graft-versus-Host Disease, Nonrelapse Mortality, and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis

The effect of chronic graft-versus-host disease (cGVHD) on the risk of nonrelapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research (CIBMTR) analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (age ≥60 years). We included 4429 adults age ≥40 years who underwent a first HLA-matched peripheral blood stem cell alloHCT for acute myelogenous leukemia or myelodysplastic syndrome between 2008 and 2017. We compared outcomes of 4 groups-older adults (≥60 years) and younger adults (40 to 59 years) with cGVHD and older and younger adults without cGVHD-to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse, and overall survival (OS). We treated cGVHD as a time-dependent covariate. The severity of cGVHD was based on the CIBMTR clinical definitions. cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher for older adults versus younger adults. Adults who developed cGVHD as a group had longer OS compared with age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild to moderate cGVHD was associated with longer OS. Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse, and longer OS. Older adults had a higher risk of NRM, but the increased risk of NRM associated with cGVHD did not differ based on age. The development of mild to moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing the risk of relapse. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Governs GVHD and Immunosuppression Need, Reducing Late Toxicities in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant significantly reduced GVHD-incidence, while PTCy given with tacrolimus/mofetil mycophenolate (T/MMF) showed activity following allogeneic peripheral blood stem cell transplantation (alloPBSCT). Here, we report the experience of a larger cohort (85 consecutive patients) and expanded follow-up period (03/2011–12/2019) with high-risk hematological malignancies who received alloPBSCT from Human-Leukocyte-Antigens HLA-matched unrelated/related donors. GVHD-prophylaxis was PTCy 50 mg/kg (days+3 and +4) combined with T/MMF (day+5 forward). All patients stopped MMF on day+28 with day+110 = median tacrolimus discontinuation. Cumulative incidences were 12% for acute and 7% for chronic GVHD- and no GVHD-attributed deaths. For surviving patients, the 12, 24, and 36-month probabilities of being off immunosuppression were 92, 96, and 96%, respectively. After a 36-month median follow-up, NRM was 4%; median event-free survival (EFS) and overall survival (OS) had yet to occur. One- and two-year chronic GVHD-EFS results were 57% (95% CI, 46–68%) and 53% (95% CI, 45–61%), respectively, with limited late infections and long-term organ toxicities. Disease relapse caused the most treatment failures (38% at 2 years), but low transplant toxicity allowed many patients (14/37, 38%) to receive donor lymphocyte infusions as a post-relapse strategy. We confirmed that PTCy+T/MMF treatment effectively prevented acute and chronic GVHD and limited NRM to unprecedented low rates without loss of disease control efficacy in an expanded patient cohort. This trial is registered at U.S. National Library of Medicine as #NCT02300571.

Impact of CD34+ Cell Dose on Clinical Outcomes after Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from Haploidentical Donors in AML Patients. a Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

The absolute number of infused CD34+ donor cells represents a critical step towards the achievement of durable marrow engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Previous observations have reported controversial conclusions on the impact of CD34+ cell doses and post-transplant clinical end-points. We conducted a retrospective analysis on 414 adult patients (median age 54 years; range, 18-74) with acute myeloid leukemia (AML) in first (70%) and second (30%) complete remission who had received a T-cell replete allogeneic HSCT from a haploidentical donor, using peripheral blood stem cells (PBSC), between 2006-2018, based on ALWP-EBMT registry data. Graft vs. host disease (GVHD) prophylaxis was post-transplant cyclophosphamide (PT-Cy)-based in 293 (71%) patients and anti-lymphocyte serum (ATG)-based in 121 (29%) patients. Conditioning was myeloablative in 179 (43%) patients and reduced-intensity in 235 (57%) patients. Median number of infused CD34+ cells was 6.58 × 106/kg (range, 2.2-31.2). After a median follow-up of 23.3 months (range, 12.1-41.8) 2-year overall survival (OS) was 64.5% (95% CI 59.3-69.7) with a leukemia-free survival (LFS) of 57.3% (95% CI 51.8-62.7) and non-relapse mortality (NRM) of 23.3% (95% CI: 19.0-27.7). The cumulative incidence of grade II-IV and III-IV acute GVHD at day-100 were 32.3% (95% CI: 27.8 - 36.9) and 14.6% (95% CI: 11.3 - 18.2), respectively. Incidence of 2-years chronic GVHD overall and extensive were 36.3% (95% CI: 30.9 - 41.6) and 14.4% (95% CI: 10.7 - 18.6), respectively. GVHD-free/relapse-free survival was 43.5% (95% CI: 38 - 48.9) at 2-years. We found the optimal CD34+/kg threshold defining high-dose (n= 334) versus low-dose (n= 80) to be 4.96 × 106, using the Hothorn and Zeileis method (Hothorn, T. and Zeileis, A. Biometrics 2008;64(4):1263–1269). Recipients of > 4.96 × 106/kg CD34+ cells experienced lower NRM (hazard ratio [HR] 0.48; 95% CI: 0.29-0.75) and prolonged LFS (HR 0.62; 95% CI 0.43-0.90) and OS (HR 0.59; 95% CI: 0.40-0.87) than recipients of ≤ 4.96 × 106/kg CD34+ cell dose. Patients who received ATG as GVHD prophylaxis experienced less grades II-IV acute GVHD respect those in the PT-Cy cohort (HR 0.56; 95% CI: 0.36-0.87) without any differences in grades III-IV acute GVHD incidence at day 100 between the two groups. On Cox analysis, a female donor to male recipient combination was associated with higher extensive chronic GVHD incidence compared to other donor-recipient sex combinations, with CD34+ categorized according to the optimal threshold of 4.96 × 106 (HR 2.21; 95% CI: 1.23-3.97; p=0.008). AML patients who underwent a PBSC T-cell replete HSCT from haploidentical donors receiving ≥ 4.96 × 106 CD34+/kg cells experienced a lower NRM and extended survival rates compared to those receiving ≤ 4.96 × 106/kg CD34+. The latter findings may have a significant practical impact and can guide prospective approaches.

Thiotepa-Fludarabine-Treosulfan (TFT) Conditioning for 2nd Allogeneic Peripheral Blood Hematopoietic Cell Transplantation (HCT) from a Second Unrelated Donor in Patients with Acute Myeloid Leukemia (AML) Relapsed after Prior Allogeneic HCT: A Prospective Multicenter Phase II Trial

Introduction: Relapse of AML after allogeneic HCT has a dismal prognosis. Long-term survival after 2nd allogeneic HCT has been described in selected patients. Here we tested a specific protocol with a fixed drug combination for myeloablative conditioning and GvHD prophylaxis for 2nd allogeneic HCT from a different unrelated donor. (EudraCT no.: 2012-005414-18, German Clinical Trials Registry no.: DRKS00005126)Methods:Aim of the trial was to show efficacy and safety of a 2nd alloHCT from an unrelated donor after a uniform conditioning with Treosulfan 3x12gm/m2, Fludarabin 3x30mg/m2, and Thiotepa 3x 5mg/kg (TFT), and GvHD prophylaxis with cyclosporine A (CyA) /Mycophenolate and ATG-F (Neovii) 3x10mg/kg. Eligible were adult patients with AML, ECOG ≤ 2, with sensitive or refractory hematologic relapse (≥ 20% blasts) > 6 months after a prior allogeneic HCT , including secondary (s) and/ or tAML. CR prior 2nd HCT was no prerequisite.The primary endpoint of the study was disease-free survival (DFS) defined as being alive and free of disease at 1 year post 2nd HCT. Secondary endpoints were relapse, relapse mortality (RM), NRM, overall survival (OS), acute GvHD, chronic GvHD, engraftment, and adverse events. According to the Fleming one-stage design, 50 evaluable patients had to be included. If 16 or more patients were alive and free of disease at 1 year post 2nd SCT, the regimen could be considered as successful for evaluation in further trials. With this decision rule, it can be shown at one-sided α=0.1 that the probability of DFS at 1 year post 2nd HCT is higher than 23% with a power of 90%, when it is at least 40%. This is a first analysis of the study covering the first year after 2nd HCT of each patient. The analysis is based on the full analysis set, which includes all patients, for whom the conditioning regimen TFT and the GvHD prophylaxis regimen CyA, MPA/MMF, ATG-F has started, and for whom allogeneic HCT from an unrelated donor has been performed.Results: Fifty-two patients were registered for the study from 25th March 2014 up to 10th March 2017 from 9 German centres. The full analysis set includes 50 patients (median age 53.5 years). ECOG was median 1. Donors for 1st allo HCT had been related (n=11 (22.0%)) or unrelated (n=39 (78.0%)) (n=48 PBSCT, n=2 bone marrow). Conditioning for 1st HCT was myeloablative in 23 (46.0%) patients. After 1st HCT, the rate of acute GvHD I-IV was 34.0%, and of chronic GvHD was 40.0%. Median time from 1st HCT to relapse was 17.2 months and from relapse after 1st HCT to 2nd HCT 2.5 months. Thirty-six (72%) patients had received induction chemotherapy for relapse prior to 2nd HCT, 11 (22.0%) patients had received azacytidine or decitabine, and 11 (22.0%) had received donor lymphocyte infusions (DLI). Remission status prior to 2nd HCT was complete remission in 16 (32.0%) patients, chemo-refractory relapse in 33 (66.0%), one patient was in partial remission.With regard to the primary endpoint, 23 (46%, 95%-CI (31.8-60.7%) of the patients were alive and free of relapse at 1 year after 2nd SCT. With regard to the secondary endpoints at 1 year, the cumulative incidence of relapse (95%-CI) was 26 (17-42)%, 9/50 patients (18 (10-33)%) died after relapse of AML, NRM was 14/50 patients (28 (18-44)%, cause: infection n=6, infection after aGvHD n=6, PTLD n=2), OS was 54 (39-66)%. Four patients are alive after relapse. aGvHD rate was 54 (42-70)%, aGvHD III-IV 26 (16-42)%, cGvHD 26 (16-42)%, extensive cGvHD 20 (12-35)%, engraftment rate with ANC > 1.0 x 103/µl was 92 (85-100)%, with platelets > 20 x 103/µl was 80 (70-92)%, and with platelets > 100 x 103/µl was 66 (54-81)%. After 1 year, 4 patients had received DLI for prophylaxis, and 5 patients for mixed chimerism as per protocol.Conclusion:Second alloHCT with an ablative double alkylator containing conditioning regimen with Thiotepa, Fludarabine, and Treosulfan is feasible and can result in sustained disease control in patients with AML relapse after a first alloHCT, and therefore seems to be a valid option in this otherwise detrimental setting. DisclosuresFinke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria. Burchert:Novartis: Research Funding; Bayer: Research Funding; AOP Orphan: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Schub:Affimed: Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Post-Transplant Cyclophosphamide and Tacrolimus–Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571.

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

Rapid donor T‐cell engraftment increases the risk of chronic graft‐versus‐host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes

The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho-hematopoietic engraftment. The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838).

Higher infused CD34 + cell dose and overall survival in patients undergoing in vivo T-cell depleted, but not t-cell repleted, allogeneic peripheral blood hematopoietic cell transplantation

Understanding the effect of cellular graft composition on allogeneic hematopoietic cell transplantation (AHCT) outcomes is an area of great interest. The objective of the study was to analyze the correlation between transplant-related outcomes and administered CD34+, CD3+, CD4+ and CD8+ cell doses in patients who had undergone peripheral blood, AHCT and received either in vivo T-cell depleted or T-cell replete allografts. Comparison of consecutive patients who underwent peripheral blood AHCT in our institution between January 2003 and December 2009. The cohort of 149 patients was divided into two groups; non T-cell depleted (NTCD) (n=54) and T-cell depleted (TCD) (n=95). Study endpoints were overall survival (OS), progression free survival (PFS), engraftment kinetics (neutrophil and platelet recovery), incidence of acute graft versus host disease (acute GVHD), chronic GVHD, nonrelapse mortality (NRM) and disease relapse. Multivariate analysis showed that higher infused CD34+ cell dose improved OS (relative risk 0.58, 95% CI 0.34-0.98, P=.04), PFS (relative risk 0.59, 95% CI 0.35-1.00, P=.05) and NRM (relative risk 0.49, 95% CI 0.24-0.99, P=.048) in the TCD group. By multivariate analysis, there was no difference in engraftment, grades II-IV acute GVHD, extensive chronic GVHD and relapse in the two groups relative to the infused cell doses. There was a trend towards improved OS (relative risk 0.54, 95% CI 0.29-1.01, P=.05) with higher CD3+ cell dose in the TCD group. Our findings suggest that higher CD34+ cell dose imparts survival benefit only to in vivo TCD peripheral blood AHCT recipients.

Platelet and Red Blood Cell Utilization and Transfusion Independence in Umbilical Cord Blood and Allogeneic Peripheral Blood Hematopoietic Cell Transplants

Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range: 2-45 days, and PBSC 14, range: 3-34 days), only 135 of 229 (59% cumulative incidence) achieved red blood cell (RBC) independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 versus PBSC 14 days) and in patients who had received a prior transplant (median 48 versus 32 days). Patients who received UCB grafts required more RBC through day 60 post-HCT (mean UCB 7.8 (95% confidence interval [CI] 6.7-8.9) versus PBSC 5.2 (3.7-6.7) transfusions, P = .04), and more platelet transfusions (mean 25.2 (95% CI 22.1-28.2) versus 12.9 (9.4-16.4), P < .01) compared to PBSC recipients. Patients receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post-HCT compared to reduced-intensity conditioning (RIC) (7.4 versus 6.2, P = .30 for RBC; 23.2 versus 17.5, P = .07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.

Pharmacokinetically Targeted Intravenous Busulfan Combined with Fludarabine (BuFlu) as Conditioning Prior to Allogeneic Peripheral Blood Hematopoietic Cell Transplant: Pretransplant Predictors of Outcomes.

Abstract 3347Poster Board III-235We report here our experience with 145 consecutive patients (pts) treated with IV busulfan and fludarabine (BuFlu) as conditioning prior to allogeneic hematopoietic cell transplant (HCT). Bu was dosed at 130mg/m2/day on days 1 and 2 with pharmacokinetic (PK) targeting for days 3 and 4; the dose of Flu was 40mg/m2/day for 4 days. The median age was 48 (range 22-68) years. Median HCT Comorbidity Index (HCT-CI) was 3 (range 0-9) and median Karnofsky performance status (KPS) was 100% (60-100%). Sixty-two pts received grafts from HLA matched siblings, 61 from matched unrelated donors (MUD), and 22 from 1 antigen/allele mismatched MUD (mMUD). Disease status was categorized in 50 pts as standard risk (acute leukemia in CR1 or CML in CP1) and in 91 pts as high risk (including acute leukemias > CR1, CML.>.CP1, MDS, MPD, lymphoma, myeloma, and CLL). 4 pts had aplastic anemia. Bu doses were targeted to a daily area under the concentration time curve (AUC) value of 5300 uM*min. Median actual AUC after the first dose was 5002 uM*min (range 3609-8190 uM*min) and doses 3 and 4 were adjusted in 92 pts (63%) to achieve the overall target AUC. Median total Bu dose to achieve AUC target was 520 mg/m2 (range 332-1040 mg/m2). Median Bu clearance (Cl) was 2.7 ml/min/kg (range 1.5-5.2 ml/min/kg). Maximum Bu concentrations (Cmax) after the first dose was 3315 ng/ml (range 1135-4848 ng/ml). First dose Bu AUC, Cmax, and Cl were not correlated with age, race, ethnicity, KPS, or HCT-CI. Women had significantly higher Cl than men (median 2.9 vs 2.6 ml/min/kg; p=0.001). Grade 3 or 4 elevations in hepatic transaminases occurred in 15 pts (10%), hepatic VOD/SOS in 6 pts (4%), and interstitial pneumonitis in 4 pts (3%). None of these toxicities were associated with any of the PK parameters measured. 100 day and 1 year non-relapse mortality (NRM) were 7% and 23% respectively. In multivariable analyses, neither first dose Bu AUC nor Bu Cl were associated with NRM. Having an unrelated donor (MUD: HR 2.68; p=0.025 and mMUD: HR 3.64; p=0.009) and a diagnosis of CML (HR 3.82; p<0.001) or lymphoma (HR 5.15; p=0.005) were associated with increased NRM. In multivariable analyses of relapse, only first dose AUC was significantly associated, with >6000 uM*min predictive of an increased risk of relapse (HR 2.66; p=0.007). The only significant predictor of overall and progression-free survival in multivariable analysis was disease risk. Overall and progression -free survivals at 2 years for the standard risk vs high risk groups were 61% and 57% vs 39% and 32% (p=0.04 and p=0.03, respectively). The increased risk of relapse in the high first dose AUC group may be related to an association between Bu Cl and uptake into malignant cells or the presence of a larger proportion of patients in this group with high risk features other than the predefined disease risk. We conclude that PK targeting of Bu provides a safe method of delivering high doses given that increased toxicity and NRM were not seen in pts with high first dose AUC due to dose adjustment. Disclosures:Perkins:PDL BioPharma: Research Funding. Off Label Use: IV Busulfan and Fludarabine for pre-transplant conditioning. Fernandez:Otsuka: Consultancy. Field:PDL BioPharma: Research Funding.

Safety Profile of Pharmacokinetically Targeted Intravenous Busulfan Combined with Fludarabine (BuFlu) as Conditioning Prior to Allogeneic Peripheral Blood Hematopoietic Cell Transplant

Safety Profile of Pharmacokinetically Targeted Intravenous Busulfan Combined with Fludarabine (BuFlu) as Conditioning Prior to Allogeneic Peripheral Blood Hematopoietic Cell Transplant

Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma

We compared the results of autologous and allogeneic peripheral blood hematopoietic cell transplant (HCT) in 87 patients with multiple myeloma using myeloablative preparative regimen. Autologous transplant (n=70) led to a lower 100-day transplant-related mortality (TRM) of 4% [0-9%] compared to 18% [0-36%] in allogeneic recipients (P=0.02). More frequent complete responses were seen in allogeneic recipients (64% [37-91%] vs 34% [23-45%] in autologous recipients, P=0.09). In autologous recipients, survival at 1 year was 86% [80-95%] and, it fell to 50% [47-75%] at 4 years, whereas in allogeneic recipients, survival at 1 and 4 years remained at 64% [40-87%]. In patients surviving more than one year, 4-year survival was superior in allogeneic (100%) vs autologous recipients (58% [41-75%], P=0.02). A trend toward higher relapse was seen in autologous transplant patients (73% [55-90%] vs 37% [11-63%] in allogeneic transplant patients, P=0.1). We observed good tolerance of myeloablative conditioning regimen followed by either autologous or allogeneic transplant. Although autologous HCT is associated with lower TRM, allogeneic HCT has acceptable TRM, and is more likely to provide a sustained response. Allogeneic HCT may be suitable in younger patients, soon after diagnosis, and in those with chemosensitive disease.

Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose

AbstractThe influence of graft composition on clinical outcomes after reduced-intensity conditioning is not well-characterized. In this report we prospectively enumerated CD34+, CD3+, CD4+, and CD8+ cell doses in granulocyte colony-stimulating factor–mobilized peripheral blood mononuclear cell (G-PBMC) allografts in 63 patients who received transplants following non-myeloablative conditioning with total body irradiation 200 cGy plus fludarabine as treatment for malignant diseases. Donors were HLA-identical siblings (n = 38) or HLA-matched unrelated individuals (n = 25). By univariate analyses G-PBMC CD8+ T-cell dose in at least the 50th percentile favorably correlated with full donor blood T-cell chimerism (P = .03), freedom from progression (P = .001), and overall survival (P = .01). No G-PBMC cell dose influenced grade II to IV acute or extensive chronic graftversus-host disease. In multivariate analysis only G-PBMC CD8+ T-cell dose (P = .003; RR = 0.2, 95% CI = 0.1-0.6) was associated with improved freedom from progression. Infusion of low G-PBMC CD8+ T-cell dose for reduced-intensity allografting may adversely affect T-cell engraftment and survival outcome.

Engraftment and Survival Following Non-Myeloablative Allogeneic Peripheral Blood Hematopoietic Cell Transplantation for Malignant Diseases Is Affected by CD8+ T-Cell Dose.

The influence of graft composition on clinical outcomes after non-myeloablative allogeneic hematopoietic transplantation is not well characterized. In this report we evaluated the influence of CD34+, CD3+, CD4+, and CD8+ cell doses on donor engraftment, graft-versus-host disease (GVHD), freedom from progression (FFP), and overall survival (OS). Patients (n=63) were given total body irradiation 200 cGy (n=8) or total body irradiation 200 cGy plus fludarabine (n=55) followed by allografting with granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC). The median age was 53 years, and donors were HLA-identical siblings (n=38) or HLA-matched unrelated individuals (n=25). Almost all patient were treated for a hematologic malignancy (n=60), with 30 patients (48%) characterized as having advanced diseases. G-PBMC cell doses were prospectively enumerated by FACS analysis at the time of collection. Median donor G-PBMC cell doses were 7.4x106 CD34+/kg (range: 1.9–17.7), 3.2x108 CD3+/kg (range: 0.8–6.4), 2.1x108 CD4+/kg (range: 0.4–4.1), and 1.1x108 CD8+/kg (range: 0.2–3.4). By univariate analysis only G-PBMC CD8+ T-cell dose ≥ the 50th percentile favorably correlated with attainment of full donor blood T-cell chimerism (P = .03). The incidences of grade 2–4 acute GVHD was 16.3% (95% CI: 6.9–25.8) and extensive chronic GVHD was 42.9% (95% CI: 27.8–57.9). No G-PBMC cell dose significantly influenced grade 2–4 acute or extensive chronic GVHD. With a median follow-up of 13 months (range: 5–45), estimates for FFP was 53.7% (95% CI: 37.7–69.7) and OS was 33.4% (95% CI: 17.4–49.4). G-PBMC CD8+ T-cell dose ≥ the 50th percentile T-cell dose was favorably prognostic for both FFP (P = .001) and OS (P = .01). Survival curves for FFP and OS are shown in Figure 1. Extensive chronic GVHD also predicted better FFP (P = .02), but in multivariate analysis only G-PBMC CD8 + T-cell dose (P = .004; RR = 0.2, 95% CI = 0.1–0.6) was associated with improved FFP. Infusion of low G-PBMC CD8+ T-cell dose for non-myeloablative allografting with total body irradiation 200 cGy plus fludarabine may adversely affect donor T-cell engraftment, disease progression and survival outcomes. [Display omitted]