Chronic GVHD Is Not Increased with the Use of PBSC Instead of Bone Marrow for T-Replete HLA-Haploidentical Transplanation Using Post-Transplant Cyclophosphamide : A Multivartiate Analysis of 116 Consecutive Transplants from a Single Center

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3922-3922
Author(s):  
Asad Bashey ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Katelin Connor ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Cox Model ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Increased Risk

Abstract HLA-haploidentical related donors (HID) are a potential option for patients who need an allogeneic haploidentical transplant but lack an optimally matched conventional donor (HLA-identical sibling or 8 of 8 HLA-A, B, C, DRB1 matched unrelated donor) (MRD and MUD respectively). The Baltimore approach to HID transplantation that uses T-replete grafts and post-transplant cyclophosphamide to control alloreactivity (HIDT-ptCy) has demonstrated promising outcomes and appears to be safe and effective. Bone marrow (BM) grafts have almost exclusively been used for HIDT-ptCy in Baltimore. Early studies from other centers have demonstrated that G-CSF mobilized PBSC may be safely used for HIDT-ptCy (Castagna et al BBMT 2014, Raj et al BBMT 2014). HIDT-ptCy using BM grafts has been associated with relatively low rates and severity of chronic GVHD. However, it is unclear whether the use of PBSC for HIDT-ptCy will be associated with higher rates of chronic GVHD than with BM grafts as has been demonstrated for MRD and MUD transplants. We analyzed 116 consecutive HIDT-ptCy first transplants (BM=64, PBSC=52) performed for hematologic malignancies at our center. Identical supportive care measures were utilized for BM and PBSC patients. GVHD was prospectively documented using established criteria by a single dedicated nurse. NIH consensus criteria were used for chronic GVHD. Gray's test was used to compare the cumulative incidences of GVHD. A Cox model was used in multivariate analysis of GVHD outcomes. Characteristics of the patients are demonstrated in Table 1. Patients undergoing HIDT-ptCy using PBSC were significantly more likely to receive myeloablative conditioning, were younger, were less likely to have been transplanted prior to 2007. Although the frequency of diagnoses differed, the Dana-Farber/CIBMTR Disease Risk Index (DRI) was not significantly different between the two groups. Median follow-up for BM and PBSC patients was 44 m and 25 m. Six month cumulative incidences of acute GVHD grades 2-4 were 39% and 42% and grades 3-4 were 14% and 21% for BM and PBSC grafts respectively. The two year cumulative incidences of extensive chronic GVHD were 38% and 45% and for severe chronic GVHD were 8% and 6% respectively (p=NS for all BM vs PBSC comparisons). In a multivariate analysis assessing effects of patient, disease and transplant variables on GVHD outcomes, graft type i.e. PBSC vs BM was not a significant predictive factor for acute or chronic GVHD. These data demonstrate that unlike the case following MRDT and MUDT, G-CSF mobilized PBSC grafts are not associated with an increased risk of chronic GVHD than BM grafts following HIDT-ptCy. Severe chronic GVHD is very uncommon with both types of graft following HIDT-ptCy and is an indication of the effectiveness of ptCy in controlling alloreactivity in this setting. Disclosures No relevant conflicts of interest to declare.

scholarly journals Use of the Dana-Farber/CIBMTR Disease Risk Index (DRI) to Compare Outcomes of T-Replete HLA-Haploidentical Transplants Using Post-Transplant Cyclophosphamide to Matched Sibling and Matched Unrelated Donor Transplants : A Multivariate Analysis of 498 Contemporaneous Allogeneic Transplants from a Single Center

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1203-1203
Author(s):  
Asad Bashey ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Katelin Connor ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Term Survival ◽  
Post Transplant

Abstract Introduction: Many patients, especially those from of ethnic minorities or mixed race, lack timely access to an HLA-identical sibling or 8 of 8 matched unrelated donor for allografting. HLA-haploidentical related donors (HID) are almost universally and rapidly available, and may be a valid alternative donor option for these patients. The approach developed in Baltimore that uses T-replete grafts from HID and post-transplant cyclophosphamide (ptCy) to control alloreactivity, (HIDT-ptCy), has demonstrated promising outcomes. No randomized comparisons of HIDT-ptCy to HLA-identical sibling transplants (MRDT) and matched unrelated donor transplants (MUDT) have been reported. We previously reported equivalent outcomes for HIDT-ptCy, MRDT and MUDT in a retrospective analysis (Bashey et al J. Clin Oncol 2013 vol 31:1310). In the current study we have used the recently developed and validated Dana-Farber/CIBMTR Disease Risk Index (DRI) (Armand et al Blood 2014 vol 123: 3664) as a measure of patient disease risk together with other patient, disease and transplant parameters in a multivariate analysis to compare outcomes of HIDT-ptCy to MRDT and MUDT in 498 consecutive patients who underwent a first allogeneic transplant for hematologic malignancy [MRDT (n=186), MUDT (n=196) and HIDT-ptCy (n=116)] at our center between 2/2005 and 2/2014. Methods Ex-vivo T-depleted transplants and cord blood transplants were excluded. Supportive care measures were identical between the three groups. Cumulative incidences of acute and chronic GVHD were estimated with death being treated as the competing risk. Cox proportional hazards models, stratified on the three transplant groups, were developed using overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), relapse as endpoints and other parameters as covariates. Adjusted survival and incidence of a transplant were calculated as the average survival and incidence of the given transplant, weighted by proportion of each patient prognostic factor in the pooled samples. GVHD was prospectively documented by a single dedicated nurse using established criteria including NIH consensus criteria for chronic GVHD. Results: Characteristics of the HIDT-ptCy patients were as follows: median age 51 (20-74); male 54%; regimen- myeloablative (40%) non-myeloablative (60%); graft- PBSC (80%) bone marrow (20%) ; Diagnoses- AML 41%, ALL 17%, CLL 11%, MDS/MPD 11%, NHL 10%, HL 9%, CML 9%, MM 2%; DRI- low (20%), intermediate (41%), high (34%), very high (5%); Sorror HCT-comorbidity index - 0 (29%), 1-3 (55%), >4 (16%); 14% had prior autografts. Median HLA mismatches were 5/10 (range 2/10 to 5/10). When compared to MRDT and MUDT, HIDT-ptCy patients had similar characteristics but were less likely to have myeloablative conditioning (p<0.001) and were more likely to have a BM graft (p<0.001). Median follow-up of surviving patients following MRDT, MUDT and HIDT-ptCy were 49m, 31m and 32 m. On multivariate analysis covariates found to have a significant effect upon the chosen endpoints were - OS: DRI, regimen intensity, age, HCT-CMI; DFS: DRI, regimen intensity, year of transplant, age &HCT-CMI; NRM: regimen intensity, diagnosis, age; Relapse: DRI, year of BMT, age. Adjusted estimates for OS, DFS, NRM and relapse are shown in Fig 1. For MRDT, MUDT and HIDT-ptCy respectively, adjusted estimates are as follows: NRM at 1year 10%, 10% and 9% and 2yrs 15%, 16%, 15%, Relapse at 1year – 21%, 29%, 30% and 2 yrs -27%, 35%, 32%; OS at 1 yr 80%, 78%, 75% and 2 yrs – 69%, 61% , 62%. DFS at 1 yr – 67%, 63%, 62% and 2 yrs – 57%, 50%, 54% (p=NS for all endpoints). The cumulative incidences of acute GVHD at 180 days were: grade 2-4 – 28%, 48% and 41% (p=0.055 MUDT vs HIDT and p=0.003 MRD vs HIDT); grade 3-4 – 9%, 19% and 17% (p=NS MUD vs HIDT, p=0.022 MRD vs HIDT) and chronic GVHD at 3 yrs were: extensive- 54%, 57%, 41% (p=0.004 MUD vs HIDT, p=0.014 MRD vs HIDT); NIH severe – 16%, 16%, 8% (p=0.035 MUD vs HIDT, p=0.044 MRD vs HIDT). Conclusions: These data demonstrate that HIDT-ptCy produce similar long-term survival, DFS, NRM and relapse to MRDT and MUDT. Rates of extensive and severe chronic GVHD are lower following HIDT-ptCy than MRDT and MUDT. HIDT-PtCy should be considered a standard-of-care option for patients who may benefit from allografting but lack a conventional donor. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Favorable Results of Allo-HSCT from MRD in Patients with Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5934-5934
Author(s):  
Miroslaw Markiewicz ◽  
Monika Dzierzak-Mietla ◽  
Patrycja Zielinska ◽  
Agata Wieczorkiewicz-Kabut ◽  
Sylwia Mizia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Collagen Type ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Graft Loss ◽  
Chronic Phase ◽  
Curative Treatment ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Introduction: Myelofibrosis (MF), chronic myeloid malignancy associated with shortened survival, in majority of patients develops de novo as Primary MF, but also polycythemia vera (PV) or essential thrombocythemia (ET) may progress into post-PV or post-ET MF. Although management of MF includes several treatment options, the only potentially curative treatment approach in MF is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Aim of this study was to evaluate the results of allo-HSCT in patients with MF treated in Katowice, Poland. Material and Methods: 27 pts (14 male and 13 female) with median age 51 years (range 21–63) were treated with allo-HCT due to PMF (20), post-PV (4) or post-ET (3) MF. 11,7,11,26 and 41% of pts had DIPSS 0,1,2,3 and 4, respectively. Median bone marrow cellularity was 70% (10-100%), fibrosis was collagen-type (14 pts including 2 with osteosclerosis), reticulin (10) or it was not specified (3). Splenomegaly was present in all pts: 13-20 cm (14 pts), > 20 cm (13 pts). JAK2V617F point mutation was present in 18 pts. Karyotype was available in 14 pts: in 9 normal, in 5 with variable abnormalities. Median time from diagnosis to allo-HCT was 1.5 (0.4–9.5) years. 16 pts (59.3%) received cells from HLA-matched related donor (MRD), 11 pts (40.7%) from unrelated donor: 10/10 (9) or 9/10 (2) HLA-A,B,C,DR,DQ alleles matched. Reduced intensity conditioning (RIC) was used in 26 pts, 1 patient received myeloablative conditioning (MC). Sources of stem cells were: peripheral blood (21), bone marrow (4) and both (2). All pts but one had chronic phase of MF at time of transplantation. Results: 14/27 (52%) pts are alive at median 3.4 (0.4-5.4) years after allo-HSCT: 11/16(69%) from MRD and 3/11(27%) from MUD, p=0.032. Graft failure, graft loss or PRCA were observed in 3, 5 and 1 pt, respectively. Absolute neutrophil count >0.5×109/L and platelet count >50×109/L were achieved at median 16 and 28 days, respectively. 12/27 (44%) pts reached complete blood count of Hb>10 g/dl, Plt>100 G/l and WBC>3.5 G/l; 11 of them (92%) are alive. 6/27 (22%) pts remained either RBC or PLT transfusions dependent post-transplant; 3 of them (50%) died. 9/27 (33%) pts remained both RBC and PLT transfusion dependent and all of them died. JAK2V617F mutation was completely eradicated in 11/16 evaluated previously positive patients (69%), decreased in 4 (25%) and stable in 1(6%) pt. Acute graft-versus-host disease (aGVHD) III-IV developed in 5/27 (19%) and extensive chronic GVHD in 5/19 (26%) pts. Relapse occurred in 4 pts and was treated with subsequent second transplant (in 1 pt thereafter by 3-rd allo-HSCT). Spleen length decreased at median by 5 (0.3-9.2) cm. Out of 7 pts with initial collagen fibrosis who were evaluated post-transplant, 1 had no fibrosis, 5 reticulin type and only in 1 pt collagen fibrosis was stable. Out of 3 pts with initial reticulin fibrosis it disappeared in 2 and progressed to collagen type in 1. Causes of death were GVHD (5 pts: 3 aGVHD, 2 cGVHD) and pancytopenia with either infection (7 pts) or CNS hemorrhage (1 pt). Conclusions: Allo-HSCT, the only curative treatment of myelofibrosis, provides chance of long survival, regression of the disease (lower stage of fibrosis, JAK2V617F eradication) and improved quality of life (transfusion independency, decreased splenomegaly). Transfusion independency may indicate good outcome. Favorable results are observed after allo-HSCT from MRD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cord Blood Transplants Supported By Unrelated Donor CD34 Progenitor Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4646-4646
Author(s):  
Alexandra Gomez-Arteaga ◽  
Danielle Guarneri ◽  
Usama Gergis ◽  
Jingmei Hsu ◽  
Sebastian A. Mayer ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Unrelated Donors ◽  
Second Degree

Abstract Introduction: Umbilical cord blood (UCB) transplant supported by third party CD34-selected cells results in rapid count recovery, UCB mediated GVL effects and low rates of chronic GvHD. For patients lacking haplo-identical relatives, other sources of CD34 progenitors are needed. Methods: We identified partially matched unrelated donors for patients lacking suitable haplo-identical donors -including second-degree relatives - and who otherwise were candidates for haplo-cord transplant. Most were treated on prospective studies (clinicaltrials.gov 00943800 and 01810588). For 5 patients, UCB were obtained through NCT01351545. Results: Between 12/2014 to 7/2018 of 126 candidates for haplo-cord transplant, 26 (21%) had no suitable related donor. Most common reasons were: no first or second degree partially matched donors, ill or unavailable relative, high titers of HLA-antibodies against all relatives, or evidence of hematological familial hereditary syndrome. Diagnoses were: 16 AML/MDS, 5 ALL, 2 MPN, 1 NHL, 1 plasma cell leukemia and 1 SAA. Median age was 57 (24-75). 50% were women. 42% non-Hispanic white (NHW), 19% non-Hispanic blacks (NHB), 19% Hispanic, 8% other minorities. CIBMTR Disease Risk Index (DRI): 46% intermediate, 38% high and 8% very high. Median HCT-CI was 3.5 (25%-75% IQR 2-6). Conditioning: 16 Flu/Mel/TBI (94% 400cGray), 8 Flu/Mel,1 Flu/Cy, 1 Etoposide/TBI. All except 1 received ATG 4.5 mg/kg and all received post-transplant Tacrolimus and MMF. UCB matching was 4/8, 5/8, 6/8 or 7/8 HLA in 12%, 27%, 23%, and 38%, respectively. HLA matching for unrelated haplos was 5-6/12, 7-8/12, >9/ 12 HLA in 15%, 54% and 19%, respectively. For UCB, median cells collected were 2.1 (range1.1-4.0) ×107 TNC/kg. CD34 cell dose of unrelated donor graft was 3-5 ×106 CD34/kg. Median time to ANC engraftment was 11 days (range 9-35) and platelet engraftment was 18 days (range11-124). Chimerism on day 56 are shown in figure 1. There were three patients with graft failures: Pt #5 with complete graft rejection, autologous reconstitution, but ongoing clinical remission that persists to date (Day+ 1223); Pt #13 with graft failure and subsequent relapse, rescued with second UCB HSCT but died of progression of disease; and pt #18 who died from infectious complications after graft failure. Acute GvHD occurred in 35% of patients (4 Grade I-II, 4 Grade III, and 1 Grade IV). cGvHD was rare: One patient with mild severity and a second with severe lung involvement. After a median follow up of 209 days, 6 months cumulative incidence of relapse (CIR) was 16% and non-relapse mortality (NRM) was 20%. Median OS was 14 months (95%CI 7-27). Conclusion: 20% of adults without matched related or unrelated donors, also lack suitable first or second degree haplo-identical donors. UCB transplant with partially matched unrelated donor accessory cells provides an alternative for transplantation. Engraftment is rapid, rates of acute GVHD are acceptable and incidence of chronic GVHD is very low. Prolonged survival is encouraging in this patient cohort with adverse characteristics and who would not be candidate for haplo-identical HSCT. Disclosures No relevant conflicts of interest to declare.

Incorporation of Posttransplant Cyclophosphamide (PCy) As Part of Standard Immunoprophylaxis (IP) for All Allogeneic Transplants: A Retrospective, Single Institution Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4485-4485
Author(s):  
Dennis Cooper ◽  
Jackie Manago ◽  
Vimal Patel ◽  
Dale Schaar ◽  
Tracy Krimmel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Number Of Patients ◽  
One Year ◽  
Disease Free

Background: The incorporation of PCy in IP has allowed transplantation of stem cells from haploidentical (HI) family members such that nearly all patients have a potential donor. Thus far, HI stem cell transplantation with PCy appears to yield comparable results to matched unrelated (MUD) and matched sibling donors (MSD) who have been treated with conventional GVHD regimens, but with less chronic GVHD (cGVHD). Particularly in light of the low incidence of cGVHD, which has not been achieved with other IP strategies after T cell-replete products, PCy is being investigated after MUD and MSD transplantation where complications from cGVHD remain the major cause of non-relapse mortality. A recent study from the BMTCTN showed that in patients conditioned with reduced intensity regimens and who received MSD and MUD stem cells, the addition of PCy to standard IP (SIP) was superior to either bortezomib or maravoric in the composite endpoint of graft-versus-host disease-free, relapse-free survival (GRFS). However, this study did not include patients who received ablative conditioning regimens and did not report on the percentage of patients who were disease-free and off immunosuppression (DFOI) at 1 year after transplant. In the present study, we have compared our experience with the addition of PCy for essentially all allogeneic stem cell transplants treated over a 2 year period with the results of patients treated with SIP in the prior two year span. Outcomes of interest included one-year overall survival (OS) and one-year GRFS as well as the percentage of patients DFOI at one year. Methods: With the exception of patients receiving umbilical cord blood transplants, beginning in April 2016, all but two patients who received allogeneic transplants were given mobilized peripheral blood stem cells and then treated with PCy on days +3 and +4 followed by tacrolimus and mycophenolate on day 5. In the absence of GVHD, mycophenolate was stopped at days +35-50 and tacrolimus was tapered beginning after day +100 unless there was low donor chimerism or a suspicion of relapse in which case tacrolimus could be tapered sooner. In order to have at least one-year follow-up, the last patient included in the study was treated before April 2018. During this time period, MSD were prioritized over MUD which in turn were chosen over haploidentical donors. For comparison, we looked at the prior 2 year period (2014-2016) in which patients were treated with SIP (including ATG in patients who received MUD stem cells). Because of a higher percentage of patients with an advanced disease risk index (DRI) in the years 2014-2016, we restricted our analysis in the SIP cohort to those patients with low and intermediate risk disease but included all patients in the more recent period who received PCy. Results: There were 68 patients treated in the PCy group, including 2 patients who received PCy after HI transplants in the years 2014 and 2015. After eliminating patients with high DRI there were 40 patients in the earlier SIP cohort of patients. The resulting patient groups were similar with respect to median age (53) and diagnosis (approximately 80% of patients with AML and ALL). There was a slightly higher percentage of patients in the SIP group with hematopoietic cell transplantation-comorbidity index scores of 3 or more (52.5 vs 48.5). In the PCy group the number of patients with early, intermediate and advanced DRI were 2, 53 and 13, whereas in the (modified) SIP category 2 patients had a low DRI and 38 had intermediate DRI. In the PCy group, HI donors comprised 26.5% of the total compared to 19.1% MSD and 54.4% MUD donors. In the SIP group, MSD and MUD donors accounted for 30% and 70% of the donors. One-year percentages of OS, GRFS and DFOI were 79.4, 47.1 and 44.1 in the PCy group compared to 72, 45 and 35 in the SIP cohort. If the analysis of the PCy group is limited to the 50 patients with MSD and MUD donors (as in the SIP cohort), the one-year OS, GRFS and DFOI are 88, 52 and 52. Conclusions: PCy in combination with SIP resulted in at least comparable results as SIP despite the inclusion of 19% of patients with a high DRI and 26.5% HI donors. The results with the addition of PCy are excellent in patients with MSD and MUD donors with more than half of the patients GRFS and DFOI at one year. Future studies on GVHD prophylaxis should report DFOI as the latter status may be the best platform for posttransplant strategies aimed at eliminating minimal residual disease and for improving QOL. Disclosures No relevant conflicts of interest to declare.

Allogeneic Bone Marrow Transplantation From Unrelated Donors in Multiple Myeloma: A Study from the Italian Bone Marrow Transplantation Donor Registry

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2009-2009
Author(s):  
Benedetto Bruno ◽  
Roberto Passera ◽  
Francesca Patriarca ◽  
Francesca Bonifazi ◽  
Vittorio Montefusco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Stem Cell Source ◽  
Cell Source ◽  
Reduced Intensity

Abstract Abstract 2009 To evaluate the role of allografting from unrelated donors in the treatment of myeloma we conducted a retrospective study through the Italian Bone Marrow Transplantation Donor Registry. Overall, from 2000 through 2009, 196 myeloma patients, median age 51 years (32–67), for a total of 199 allografts, were transplanted from an unrelated donor at 34 Centers in Italy. Fifty-two (28.1%%), 69 (37.3%), and 64 (34.6%) patients were prepared for transplant with a myeloablative, a reduced-intensity and a non-myeloablative conditioning respectively. Patient characteristics of the 3 cohorts are reported in Table 1.ConditioningMyeloablativeReduced-intensityNon-myeloablativePatient number (%)52/185 (28)69/185 (37)64/185 (35)Median Age455355Previous therapy lines < 2 (%)23 (27)33 (38)30 (35)Previous therapy lines ≥ 2 (%)29 (29)36 (37)34 (34)Stem Cell Source BM (%)24 (57)18 (43)0 (0)Stem Cell Source PBSC (%)28 (19)51 (36)64 (45) Cumulative incidence of acute grade II-IV graft-versus-host-disease (GVHD) was 46.4% whereas chronic GVHD was 45.1%. There was no difference in GVHD incidence among the 3 cohorts defined by type of conditioning. Complete and partial remissions in patients who survived at least 3 months post-transplant were 27% and 28% for an overall response rate of 55%. At a median follow up of 32 (0–118) months post-transplant, in the entire study population, median OS from diagnosis was 70.6 months while OS and EFS from the allograft were 18.9 and 14.9 months. Overall, the cumulative incidence of transplant related mortality (TRM) was 29.6% at 1 year and 32.4% at 5 years post-transplant. OS from diagnosis and EFS from transplant were 70.6 and 28.2 months; 66.8 and 9.1 months; and 111.9 and 22.4 months in patients who respectively underwent a myeloablative, a reduced-intensity and a non-myeloablative transplant. One-year and 5-year TRM was 33.3% and 35.7%, 32.2% and 34.4%, and 22.1% and 26.5% respectively. Univariate and multivariate analyses, assessed by multivariate Cox proportional hazards models, were performed for the following variables: number of previous chemotherapy lines (1,2 vs. ≥3), disease status at transplant, HLA- matched antigens (10/10 vs. 9/10 vs. ≤8/10), recipient/donor gender combinations, hematopoietic cell source (peripheral blood vs. bone marrow), conditioning (myeloablative vs. reduced-intensity vs. non-myeloablative), use of anti-thymoglobulin in the conditioning, acute GVHD, chronic GVHD, best response post-transplant, year of transplant (2000–02 vs. 2003–05vs. 2006–09). By univariate analysis, lower number of chemotherapy lines before the allograft, disease status at transplant, a fully HLA-identical donor, the use of peripheral hematopoietic cells rather than bone marrow were statistically significant variables for better OS whereas disease status at transplant, a fully HLA-identical donor, chronic GVHD (either limited or extensive) were statistically significant for better EFS. However, by multivariate analysis, only the development of chronic GVHD (HR 0.50; p<0.001) and a better response post-transplant (HR 2.11; p<0.03) were significantly associated with longer OS whereas chronic GVHD was the only variable associated with better EFS (HR 0.32; p<0.001). Acute GVHD was associated with both poorer OS (HR 2.35; p<0.001)) and EFS (HR 3.19; p<0.001). In conclusion, with a degree of caution given the retrospective nature of this study, there appears to be a strong association between both limited and extensive chronic GVHD and graft-vs.-myeloma effects. However, long term disease control remains an issue independent of the conditioning employed. Prospective trials may allow to define which patient category may most benefit from an unrelated donor allograft. Disclosures: Patriarca: Roche: Honoraria; Celgene: Honoraria; Schering-Plough: Honoraria; Janssen: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2048-2048 ◽  
Author(s):  
Paul Martin ◽  
Shuli Li ◽  
Edwin P. Alyea ◽  
Vincent T. Ho ◽  
Corey S. Cutler ◽  
...  
Keyword(s):  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Reduced Intensity Conditioning ◽  
Allogeneic Hct ◽  
Cell Dose ◽  
The Impact ◽  
Reduced Intensity

Abstract Background Mobilized 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. Methods In 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). Results There 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. Conclusions These 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.

Decreased Incidence of GvHD after Reduced Intensity Conditioning and a Fixed T-CELL Dose in Hematological Malingnancy Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5889-5889 ◽  
Author(s):  
Audrey Simon ◽  
Eddy Roosnek ◽  
Yordanka Tirefort ◽  
Yan Beauverd ◽  
Carole Dantin ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Two Factors

Abstract Introduction: To decrease graft versus host disease (GvHD), the Geneva transplantation team has performed allogeneic hematopoietic stem cell (alloHSCT) with reduced intensity conditioning (RIC) and T cell depletion (TCD) to treat hematological malignancies for older or non fit for myeloablative conditioning patients. This is a new approach of engineering stem cell products that lowers the risk of GvHD while preserving graft versus leukemia (GvL) as much as possible. Patient and methods: We report a retrospective study of 73 patients who received alloHSCT with RIC and TCD between 2001-2013. The median age was 59 years (21-70), 60% were male. Disease at transplant time was acute leukaemia for 45%, Hodgkin lymphoma and non-Hodgkin lymphoma for 24%, myelodysplastic disorders for 13%, myeloproliferative disorders for 9,3 % and multiple myeloma for 8%. Source of stem cell was peripheral in 96% of the cases. 41% of the donors were matched related donor, 37% matched unrelated donor, 19% mismatched unrelated donor and 3% mistmatched related donor. The conditioning regimen consisted on fludarabine with busulfan or melphalan and ATG. Extensive T-cell depletion was done using Campath in the bag followed by washing procedures to remove free antibody. Fixed number of CD3+ T-cell addback was given on d+1 to preserve GvL with minimal residual disease (MRD) assessment and early donor lymphocyte infusions (DLI) given if MRD positive. Doses of DLI were preserved and frozen at the time of stem cell harvest. GvHD prophylaxis was with ciclosporine and mycophenolate mofetil. Results: With a median follow up of 5 (0.5-11) years, the 5-year overall survival (OS), disease free survival (DFS), current disease free survival, relapse rate and non relapse mortality (NRM) were 41.7% (95%CI 30.7-53.7%), 38.8% (95%CI 28.8-50.8%), 39,5% (95%CI 27.7-51.7%), 45.3% (95%CI 32.7-57.2%) and 15.8% (95%CI 8.3-25.4%) respectively. The main cause of death was relapse 38.7 % followed by GvHD 17% and infection 1.3%. In this cohort, the cumulative incidence (CI) of acute GvHD was 15.1% (95% CI: 8.0-24.3%) as well as for acute GvHD grade II-IV. CI of chronic GvHD was 14.7% (95%CI:7.2-23.6%) with extensive chronic GvHD CI being 5.9% (95% CI: 1.9-13.4%). Five patients received DLI for relapses, 27 for mixed chimerism and 8 for both causes. The average number of DLI was 2. Twenty-eight patients entered CR, 4 PR and 13 did not respond to DLI. In univariate analysis, two factors GvHD before DLI and GvHD after first DLI have a tendency for favorable impact on OS respectively p=0.093 and 0.071. For DFS, two factors are significant: disease risk index and GvHD after first DLI respectively p=0.013 and 0.044. For NRM disease risk index is the only factor which is statistically significant p=0.005. For relapse no factors were significant. Discussion: Our study showed a lower rate of acute and chronic GvHD as compared to other studies with unmanipulated stem cells. However, we describe a high rate of relapse incidence and relapse mortality. We have found in univariate analysis two factors statistically significant for DFS GvHD before and after first DLI. Our cohort is a heterogeneous group with different diseases at different stages, which can explain those results. It’s a monocentric study and small number of patient can be a limit for this work. Of note, since 2009 we have changed our strategy introducing a day +100 preemptive DLI infusion in the absence of GvHD, with escalading doses of lymphocytes every 8 weeks up to 5x 107 CD3/kg in the absence of GvHD to improve response. We don’t have enough patients and follow up to draw any conclusion regarding this new strategy. To improve the outcomes, the selection of patients who may receive partial T-cell depletion should be refined, avoiding transplanting patients with high risk of relapse with this strategy. To help decision making, the revised disease risk index as presented by Armand et al. (Blood 2014;123:3664) may be useful. Disclosures No relevant conflicts of interest to declare.

Impact of Cytopenia Following Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophoshamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2281-2281
Author(s):  
Villetard Ferdinand ◽  
Stefania Bramanti ◽  
Samia Harbi ◽  
Sabine Fürst ◽  
Catherine Faucher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Conditioning Regimen ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
The Impact

Abstract Introduction Allogeneic transplantation from a haploidentical donor (HaploSCT) is an alternative strategy in the treatment of hematologic malignancies in absence of HLA-identical donor. Recent studies reported similar outcome after HaploSCT compared to HLA-identical transplantation in different settings (Bashey, JCO 2013; Wang, Blood 2015; Gosh, JCO 2016). Although survivals seemed promising after HaploSCT, hematopoietic recovery following such a mismatched transplantation could represent a limitation. Thus, our series aims to evaluate hematological recovery after HaploSCT using a post transplantation cyclophosphamide (PT-Cy) platform. Methods This retrospective monocentric study included consecutive patients with following criteria: adults with hematological malignancies; bone marrow or peripheral blood T-replete HaploSCT from 2011 to 2015; non-myeloablative (Baltimore approach) or reduced intensity conditioning (busulfan-based) regimen; PT-Cy as part of GVHD prophylaxis. Patients with primary graft failure were excluded. Absolute neutrophil count (ANC), red cells (RCT) or platelet transfusion (PT) requirements on day 30 (D30) and day 100 (D100) were analyzed among disease-free patients. We first separately evaluated the rate of patients with significant cytopenia in each lineage (defined by ANC < 1 G/L, RCT need, PT need) and searched for impact of pre-transplantation factors on cytopenia (multivariate analyses by binary logistic regression). Then, we evaluated outcome by D30- and D100-landmark analyses according to cytopenia. Results One hundred and forty six patients with a median age of 56 years (range: 19-73) were analyzed: 142 and 117 were evaluable at D30 (4 early deaths) and D100 (17 deaths, 11 relapses), respectively. At D30, 20% of patients had ANC<1G/L, 67% needed RCT and 63% needed PT. Corresponding values at D100 were 20%, 42% and 28%, respectively (Figure 1). At D30: the use of PBSC (HR 9.5, p=0.002) was significantly associated with ANC>1G/L at D30; the use of NMAC Baltimore schema (HR 0.3, p=0.012) and CD34+ cell dose > median (HR 0.4, p=0.041) decreased PT needs while hematopoietic cell transplantation comorbidity index (HCT-CI)≥3 (HR 3.3, p=0.004) was associated with PT needs; no factor was found to significantly influence RCT. At D100: Age>60 years (HR 2.4, p=0.045), female to male HaploSCT (HR 3.3, p=0.020) and HCT-CI≥3 (HR 3.7, p=0.006) were significantly associated with higher risk of RCT need; female to male HaploSCT (HR 3.6, p=0.015) and HCT-CI≥3 (HR 6.9, p=0.001) were associated with PT needs; no factor was found to significantly influence ANC. With a median follow up of 25 months (range: 5-55), cox multivariate model with adjustment by age (continuous), disease risk index (low/intermediate vs high/very high), HCT-CI (0-2 vs ≥3), conditioning regimen (baltimore vs. busulfan-based) and graft source (bone marrow vs PBSC) showed that ANC<1 G/L was strongly associated with higher NRM (HR 2.9, p=0.011) and shorter OS (HR 3.4, p<0.001), overcoming the impact of RCT and PT needs (Figure 2A and 2B). In contrast, D100 analysis showed that PT need was the most determinant factor of increased NRM (HR 13.7, p=0.013) and poor OS (HR 7.3, p=0.003), while both D100 ANC and RCT needs did not impact outcome (Figure 2C and 2D). Discussion We found that cytopenia remain a concern after HaploSCT, leading to increased NRM and OS. The absence of ANC>1G/L at D30 as well as the need of PT at D100 may be considered as a strong post transplantation factor predicting poor outcome. Some pre-transplantation factors of cytopenia have been identified, such as CD34+ cell dose, sex mismatch and graft source. Among them, some may help for donor selection while the optimal donor for HaploSCT is still unknown. Moreover, better neutrophil recovery at D30 is achieved with the use of PBSC. CD34+ optimal cell dose in this setting remains also to be determined. In addition, post transplantation events such GVHD and/or infections should be evaluate to explore their interactions with such cytopenia, aiming to develop early therapeutic interventions. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

The Disease Risk Index Predicts Outcomes Including Relapse and Survival in CD34-Selected Allogeneic HCT for Acute Leukemia and Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3498-3498
Author(s):  
Christina Cho ◽  
Patrick Hilden ◽  
Jonathan U. Peled ◽  
Scott T. Avecilla ◽  
Pere Barba ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cumulative Incidence ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Donor Type ◽  
Very High

Abstract INTRODUCTION: T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO 2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT. METHODS: This was a retrospective analysis of patients who underwent first allogeneic HCT with TCD PBSCT for AML, ALL, or MDS at a single center between 1/2000 and 12/2015. Overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (CRFS) were estimated by the Kaplan-Meier method. Cumulative incidence of relapse, non-relapse mortality (NRM), acute GVHD (aGVHD), and chronic GVHD (cGVHD) were estimated using the cumulative incidence method for competing risks. The univariate association between variables of interest and OS/RFS/CRFS was evaluated using the log-rank test; Cox regression models assessed the adjusted effect of significant covariates on OS and RFS. Given only 1 patient with very high DRI, the high/very high DRI groups were combined. Similarly, given few patients with low DRI, the low/intermediate groups were combined in multivariate analysis. RESULTS: The analysis comprised a total of 519 patients. Median age was 55 years (range 18-73). There were 302 patients (58%) transplanted for AML, 144 (28%) for MDS, and 73 (14%) for ALL. Seventeen patients had low DRI scores (3%), 431 intermediate (83%), and 71 high/very high (14%). Median follow-up among survivors was 53.1 months (range 4.6-171.0). Two-year estimates for outcomes of interest were OS 62.8% (95% CI 58.5, 66.9), RFS 58.1% (95% CI 53.7, 62.3), and CRFS 54.0% (95% CI 49.5, 58.2). The cumulative incidence of relapse at 2 years was 17.3% (95% CI 14.2, 20.7). There were 0 relapse events in patients with low DRI, whereas intermediate and high/very high DRI scores were associated with a significantly increased incidence of relapse (p &lt; 0.001), with 2 year estimates 14.7% (95% CI 11.5, 18.3) and 37.1% (95% CI 25.8, 48.4), respectively. The cumulative incidence of NRM was 24.6% (95% CI 20.9, 28.4) at 2 years. The cumulative incidence of aGVHD at 100 days was 12.5% (95% CI 9.8, 15.5) for grade 2-4 and 2.5% for grade 3-4 (95% CI 1.4, 4.1); with a cumulative incidence of cGVHD of 4.7% (95% CI 3.1, 6.7) at 1 year. NRM, aGVHD, and cGVHD did not vary with DRI. In univariate analysis, DRI was associated with significant differences in OS, RFS, and CRFS (Table 1; Figure). Additional factors associated with poorer OS in univariate analysis were HCT-CI score &gt; 0, KPS &lt; 90, donor type (matched unrelated or mismatched vs. matched related donor), and age &gt; the median of 55.3 years; HCT-CI and KPS also correlated with significant differences in RFS. On multivariate analysis (Table 2), high/very high DRI corresponded to significantly greater risk of death (HR 1.72 for OS, [95% CI 1.24, 2.40]) and relapse or death (HR 1.86 for RFS [95% CI 1.35, 2.55]), compared with low/intermediate DRI. Multivariate analysis also showed that KPS &lt; 90 was associated with worse OS and RFS, as did a higher HCT-CI score. Neither age nor donor type was significantly associated with OS in multivariate analysis. CONCLUSION: In a large cohort of patients undergoing first TCD PBSCT at a single center for acute leukemia or MDS, DRI score significantly correlated with relapse incidence as well as OS, RFS, and CRFS. We have previously shown that the HCT-CI score, which incorporates patients' baseline comorbidities, is also predictive of outcomes after TCD PBSCT. Combining these prognostic tools will serve to better select appropriate patients for TCD PBSCT, a transplant approach currently under investigation in a multicenter phase 3 trial (BMT CTN 1301). Disclosures Koehne: Atara Biotherapeutics: Consultancy.

scholarly journals Impact of Cryopreservation of Donor Grafts on Outcomes of Allogeneic Hematopoietic Cell Transplant (HCT)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Jack W. Hsu ◽  
Nosha Farhadfar ◽  
Hemant S. Murthy ◽  
Brent Logan ◽  
Stephanie Bo-Subait ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Disease Risk ◽  
Risk Index ◽  
Data Monitoring Committee ◽  
Data Monitoring ◽  
Platelet Recovery ◽  
Monitoring Committee ◽  
Increased Risk ◽  
Donor Type

Introduction: Cryopreservation of peripheral blood stem cell (PBSC) or bone marrow (BM) grafts is rarely performed, thus information about the effect of cryopreservation on graft characteristics and HCT outcomes is limited. Given the global pandemic leading to changing practices for donor graft collection and increasing utilization of cryopreservation, we evaluated the outcomes of HCT recipients who received either fresh or cryopreserved allogeneic BM or PBSC grafts. The primary endpoint was engraftment. Secondary endpoints were incidence of acute graft-vs.-host disease (aGVHD), relapse, transplant related mortality (TRM), disease free survival (DFS), and overall survival (OS). Methods: We included 7397 patients transplanted between 2013 and 2018. 1883 cryopreserved graft recipients were divided into three cohorts based on graft source and donor type: matched related (MRD) PBSC (n=1,051), matched unrelated (MUD) PBSC (n=678), and matched related or unrelated bone marrow donors (n=154). All patients received conventional calcineurin-based GVHD prophylaxis strategies. Patients who received cryopreserved grafts were matched with 5514 patients who received fresh adjusting for graft type (BM vs. PB), donor source (MRD vs. 8/8 MUD), Disease Risk Index (DRI, low risk vs. intermediate risk vs. high risk), recipient age (within 5-years) and propensity score (within 1 standard deviation from pooled sample). The propensity score was based on age, Karnofsky score, diagnosis, disease risk index, HCT-comorbidity index, and conditioning intensity. The level of statistical significance for the main analyses was p&lt;0.01 due to multiple comparisons. The reason for cryopreservation was available on a subset of URD product recipients. Results: Baseline characteristics for all cohorts are shown in Table 1. CD34+ doses reflect enumeration at infusion. In univariate analyses, rates of graft failure and neutrophil recovery at day 28 were similar for cryopreserved and fresh grafts for BM or related PBSC recipients but differed in cryopreserved vs. fresh MUD PBSC (5% vs 2%, p&lt;0.001 and 87 vs 94%, p&lt;0.001, respectively). Rates of platelet recovery within 28 days were similar in marrow cohorts, but lower with cryopreserved related (92% vs 96%, p&lt;0.001) and MUD PBSC (87 vs 94%, p&lt;0.001) grafts. In matched pair multivariable analyses, there were no significant differences in any outcomes with cryopreserved vs fresh BM grafts, irrespective of donor type. With related donor PBSC, cryopreservation was associated with decreased platelet recovery (HR=0.73, CI=0.68-0.78, p&lt;0.001) and an increased risk of both grade II-IV (HR=1.27, CI=1.09-1.48, p=0.002) and grade III-IV (HR=1.48, CI=1.19-1.84, p&lt;0.001) aGVHD, but had no impact on other outcomes. In contrast, with MUD PBSC grafts, cryopreservation was associated with delayed engraftment of neutrophils (HR=0.77, CI=0.71-0.84, p&lt;0.001) and platelets (HR=0.61, CI=0.56-0.66, p&lt;0.001), an increased risk of TRM (HR=1.4, CI=1.18-1.66, p&lt;0.001) and relapse (HR=1.32, CI=1.11-1.58, p=0.002), and decreased DFS (HR=1.36, CI=1.20-1.55, p&lt;0.001) and OS (HR=1.38, CI=1.22-1.58, p&lt;0.001) but did not affect the incidence of aGVHD. In a subset analysis of 299 URD recipients, the most common reason for cryopreservation was delays due to patient-related events, eg., additional chemotherapy, infection. These recipients had decreased OS compared to products cryopreserved for non-patient reasons (HR=0.65, CI=0.44-0.96, p=0.029). Conclusions: The retrospective nature of this analysis, and the fact that cryopreservation is likely to have been performed in recipients with a different (higher) risk profile compared to those receiving fresh products limits our ability to draw firm confusions. Despite these limitations, we conclude that cryopreservation in some patient populations may have a negative impact on engraftment and transplant outcomes. The decision to cryopreserve donor grafts, particularly PBSC grafts, should be carefully considered and highlights the need for further investigation of the effect of cryopreservation of allogeneic grafts where patient factors can be controlled for. Disclosures Farhadfar: CSL Behring: Research Funding; Incyte pharmaceutical: Other: Member of GVHD advisory forum. Frey:Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Syntax: Consultancy, Honoraria. Devine:Magenta Therapeutics: Consultancy. Shaw:Orca Bio: Consultancy. Wingard:Shire: Other: Personal Fees - serve on data monitoring committee for clinical trial; Ansun: Other: Personal Fees - serve on data monitoring committee for clinical trial; Merck: Other: Personal Fees - serve on data monitoring committee for clinical trial; Cidara: Other: Personal Fees - serve on data monitoring committee for clinical trial; ReViral: Other: Personal Fees - serve on data monitoring committee for clinical trial.

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