scholarly journals CD34+ Cell Dose Influences Survival after Allogeneic Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3329-3329
Author(s):  
Hany Elmariah ◽  
Syeda Mahrukh Hussnain Naqvi ◽  
Jongphil Kim ◽  
Taiga Nishihori ◽  
Asmita Mishra ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Cell Group ◽  
Survival Outcomes ◽  
Entire Group ◽  
High Dose ◽  
Cell Dose ◽  
Allogeneic Pbsct ◽  
Cell Groups

Introduction: Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) resulted in improved overall survival (OS) in a recent report (McCurdy, et al. BBMT. 2018). As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the optimal cell dose with this platform requires elucidation. Methods: We retrospectively evaluated 144 consecutive adult patients with hematologic malignancies treated at the Moffitt Cancer Center between 2012-2018 with allogeneic T-cell replete PBSCT followed by PTCy-based graft-versus-host disease (GVHD) prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Both myeloablative (n=87) and reduced intensity (n=57) conditioning regimens were included. For analyses, CD34+ cell dose was stratified into low (<5 x106/kg), intermediate (5-10 x 106/kg) and high (>10x106/kg). TNC was stratified as higher or lower than the median. CD3+ T cell dose was evaluated as a continuous, linear variable. Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted. RESULTS: The median follow-up for the entire cohort was 24 months. The median age at PBSCT was 58 (range: 21-76) years. Donors were haploidentical (n=72, 50%), matched unrelated (n=39, 27%), matched related (n=18, 13%), and mismatched unrelated (n=15, 10%). Median CD34+ cell dose was 8.12 x 106/kg (range: 2.27 - 22.4 x 106/kg). Stratified CD34+ dose was low for 16 patients (11.1%), intermediate for 93 patients (64.6%), and high for 35 patients (24.3%). Median CD3+ dose was 2.89 x 108 (range: 2.33 x 105 - 6.54 x 108/kg). Median TNC was 9.66 x 108/kg (range: 3.82 x 108 - 1.04 x 109/kg). Overall, successful neutrophil engraftment by day 30 was achieved in 94% (95% CI 91-98%) and platelet engraftment (>20,000/mL) by day 100 in 87% (95% CI 81-93%) of all patients. The likelihood of neutrophil recovery was similar in the high and low CD34+ cell groups, while it was higher for the intermediate CD34+ cell group (HR=1.52, 95% CI 1.0-2.2; p=0.03). Platelet recovery was similar in the intermediate and high CD34+ cell groups, but significantly lower in low CD34+ cell group (HR=0.38, 95% CI 0.2-0.8; p=0.01). CuI of grade II-IV acute GVHD at day 100 was 39% (95% CI 32-48%) and of grade III-IV acute GVHD was 10% (95% CI 6-17%). CuI of chronic GVHD at 2 years was 50% (95% CI 41-59%). The CD34+ cell dose had no significant impact on either acute or chronic GVHD. Nonrelapse mortality (NRM) at 1 year was 19% (95% CI 13-27%). By CD34+ cell dose, the rates of NRM for low, intermediate, and high dose were 46% (95% CI 25-85%), 15% (95% CI 10-25%), and 15% (95% CI 7-34%), respectively (p=0.002). Relapse rate was 30% at 2 years with no differences across dose levels. Progression free survival (PFS) probability at 2 years was 47% (95% CI 39-57%) for the entire group, 0% (95% CI 0%) for the CD34+ low group, 53% (95% CI 42-65%) for the intermediate group and 51% (95% CI 35-73%) for the high dose group (p=0.0003). Two-year OS for the entire group was 57% (95% CI 49-67%), and was inferior in the low group (0%, 95% CI 0%) with no difference between the intermediate (61%, 95% CI 50-73%) and high (67%, 95% CI 52-87%) CD34+ cell dose groups (p=0.0002). In multivariable modeling, the low CD34+ cell dose group was associated with worse NRM (HR=4.1, 95% CI 1.2-14.5, p=0.03), PFS (HR=2.9, 95% CI 1.3-6.5, p=0.01), and OS (HR=3.2, 95% CI 1.4-7.6, p=0.01) compared with the high group, while there were no differences between the high and intermediate groups. Increasing CD3+ dose was also associated with improved NRM (HR=0.8, 95% CI 0.69-0.97, p=0.02), PFS (HR=0.7, 95% CI 0.5-0.9, p=0.02), and OS (HR=0.7, 95% CI 0.5-0.9, p=0.004). TNC had no impact on survival outcomes. CONCLUSION: In patients receiving allogeneic PBSCT with PTCy, CD34+ cell doses below 5 x 106 cells/kg yielded inferior OS and PFS, attributable to higher NRM. Doses of 5-10 x 106 cells/kg and >10 x 106 cells/kg resulted in comparable outcomes. Higher CD3+ dose/kg was also associated with improved survival outcomes. Overall, this study supports targeting a CD34+ dose of >5 x 106 cells/kg for allogeneic PBSCT with PTCy. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board.

Dendritic Cell Type 2 Counts on Day 28 in HLA-Matched Related Allogeneic PBSCT Predicts the Incidence of Acute and Chronic GVHD.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2893-2893
Author(s):  
Reena M. Rajasekar ◽  
Vikram Mathews ◽  
Kavitha M. Lakshmi ◽  
Auro Viswabandya ◽  
Biju George ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cox Regression Analysis ◽  
Cell Dose ◽  
Hla Dr ◽  
Allogeneic Pbsct ◽  
The Impact

Abstract Dendritic cells (DC) are antigen-presenting cells involved in induction and regulation of immune responses. We investigated the impact of the number of infused and engrafted (day 28) dendritic cells, DC1 (lin−HLA-DR+CD11c+) and DC2 (lin−HLA-DR+CD123+) on the development of acute and chronic graft-versus-host disease (GVHD). Thirty three consecutive patients with hematological malignancies who underwent HLA-matched related G-CSF mobilized allogeneic PBSCT were included in the analysis. The mean follow up was 293 days (range: 36–417). There were 20 males and 13 females (median age: 29 years, range: 15–55). Conditioning regimen was myeloablative in 25 (Bu/Cy=13; Cy/TBI = 12) and non myeloablative in 8 patients (Flu/Mel = 7; Flu/Cy = 1). All patients received cyclosporine and short course methotrexate as GVHD prophylaxis. Three of them received steroids before day 28 for treatment of GVHD. Ten patients developed acute GVHD (grade II–IV) and 11 patients had chronic GVHD. The median DC2 count in the peripheral blood on day 28 was significantly lower among patients who developed acute GVHD as compared to those who did not and there was a trend to a lower count among patients with chronic GVHD [Table 1]. Based on the day 28 DC2 count patients were divided into a low DC2 quartile (<2.3cell/ul, n=8) and the rest were grouped as high DC2 (>2.3cell/ul, n=25). The two groups were comparable with regard to patient and graft characteristics (CD34, CD133, CD3, CD4, CD4CD45RO, CD4CD45RA, CD8, CD8CD45RO, CD8CD45RA, CD19, NK, DC1and DC2 cell dose). Patients in the low DC2 quartile group had higher probability of developing acute (P=0.000) and chronic GVHD (P= 0.022). Cox regression analysis revealed that low day 28 DC2 counts is associated with higher incidence of acute GVHD (HR=11.4; 95%CI=2.9–44.9; P=0.001) and chronic GVHD (HR=7.07; 95%CI=1.9–26.6; P=0.004). In a multivariate analysis which included other standard risk factors such as female to male transplants, conditioning regimen, CD34 and CD3 cell dose, low day 28 DC2 was found to be a risk factor for acute GVHD (HR=21.1; 95%CI=3–149.9; P=0.002) together with patient age (HR=1.1; 95%CI=1–1.3; P=0.039). DC1, DC2 counts in the graft and day 28 DC1 count did not correlate with the development of acute or chronic GVHD. Excluding patients who had developed acute GVHD before day 28 (n=3), a low day 28 DC2 count (<2.3/ul) had a positive predictive value of 80% for acute GVHD and 75% for chronic GVHD. These results suggest that the DC2 count in the peripheral blood on day 28 is a strong predictor for development of GVHD in recipients of PBSC in matched related allogeneic HSCT. Table 1: Median day 28 DC2 count and GVHD n, median DC2 x 103/ml (range) Yes No P-value Acute GVHD (II=IV) 10, 2.06(0.6–24.8) 23, 11.5(1.1–46.6) 0.004 Chronic GVHD 11, 2.4(1.1–46.6) 17, 8.19(1.6–44.9) 0.070

scholarly journals Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3320-3320
Author(s):  
Amy E. DeZern ◽  
Marianna Zahurak ◽  
Javier Bolanos-Meade ◽  
Richard J. Jones
Keyword(s):  
Graft Failure ◽  
Acute Gvhd ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
Stopping Rules ◽  
High Dose ◽  
Gvhd Prophylaxis ◽  
Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

A Randomized, Double Blind Trial, of Hydroxychloroquine for the Prevention of Graft-Versus-Host Disease after Allogeneic Peripheral Blood Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1800-1800
Author(s):  
Tom Fong ◽  
Kim Trinkaus ◽  
Douglas R. Adkins ◽  
Ravi Vij ◽  
Steven Devine ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Double Blind ◽  
Graft Versus Host ◽  
Blood Stem Cell Transplantation

Abstract Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). We previously reported low incidences of acute GVHD in unrelated donor transplant recipients who received prophylactic HCQ in addition to standard GVHD prophylaxis (BBMT2003; 9: 714–721). We herein report results of a single-institution phase III trial, in which 95 recipients of matched sibling allogeneic peripheral blood stem cell transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ or placebo starting 21 days pre-transplant and continued until d+365. HCQ was very well tolerated and not associated with side effects. The addition of HCQ had no effects on lymphocyte subsets both pre- and post-transplant. Overall, the incidence of acute GVHD was 59% in both arms, and severe acute GVHD occurred in 11% (HCQ) and 14% (placebo) (p=0.76). Sixty-one and 46% of patients developed chronic GVHD in the placebo and the HCQ arms, respectively (p = 0.15). With a median follow-up of 18 months, relapse-free and overall survivals were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single agent CSA was not associated with a reduction of either acute or chronic GVHD; additionally, no significant effects on relapses or survival were observed.

Double Unit Myeloablative Umbilical Cord Blood (UCB) Transplantation in Adults & Adolescents: High Incidence of Engraftment and Low Transplant-Related Mortality.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 826-826
Author(s):  
Juliet N. Barker ◽  
Daniel J. Weisdorf ◽  
Todd E. Defor ◽  
John E. Wagner
Keyword(s):  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Critical Determinant ◽  
Major Barrier ◽  
Neutrophil Recovery ◽  
Cell Dose ◽  
Low Incidence ◽  
Related Mortality

Abstract UCB cell dose is a critical determinant of hematopoietic recovery & survival after UCB transplantation (UCBT) & is the major barrier to adult UCBT. Therefore, we have investigated the combined transplantation of 2 partially HLA-matched UCB units to augment graft cell dose. Twenty-three patients with high-risk hematologic malignancy [median 24 yrs (range: 13–53)] received two UCB units [median infused dose 3.5 x 107 NC/kg (range 1.1–6.3); larger unit 1.9 (0.6–3.6) & smaller unit 1.5 (0.5–2.7)]. Of the 46 units used, only 3 were 6/6, 16 were 5/6 & 27 were 4/6 HLA-A,B,DRB1 antigen matched unit to the recipient. All patients received myeloablative conditioning using cyclophosphamide 120 mg/kg (60 mg/kg days −7 & −6), & TBI 1320 cGy in 8 fractions with cyclosporine-A (CSA) from day -3 for at least 6 months. In addition, the first 2 patients received ATG 15 mg/kg every 12 hours days −3 to −1 & methylprednisone (MP) 1 mg/kg every 12 hours days 5–19. Subsequent patients (n = 21) received fludarabine 75 mg/m2 (25 mg/m2 days −8 to −6) & mycophenolate mofetil 1 gm twice daily from days −3 to +30 instead of ATG/MP. All evaluable patients (n = 21) engrafted at a median of 23 days (range 15–41). At day 21, engraftment was derived from both donors in 24% and a single donor in 76%, with one unit predominating in all patients (median chimerism in day 21 BM 100%). Notably, the predominating unit had a relatively low infused cell dose [median 1.8 x 107 NC/kg (range 0.7–3.6); 1.5 x 105 CD34+/kg (range 0.6–10.4)]. While neither NC, CD34+ & CFU-GM dose, nor HLA-A,B,DRB1 match, predicted which unit would predominate, the predominating unit had a significantly higher CD3+ dose (p < 0.01). However, the NC, CD34+ & CFU-GM doses of the predominating unit were significantly associated with the speed of neutrophil recovery. For example, the median day of neutrophil recovery for patients (n=11) with a predominating unit of 1.6–10.4 x 105 CD34+/kg was day 19.5 (range 15–27) vs day 26 (range 15–41) in patients (n=10) with a predominating unit of 0.6–1.5 x 105 CD34+/kg (p=0.01). Incidences of grade II–IV & III–IV acute GVHD were 65% (95%CI: 42–88) and 13% (95%CI: 0–26) at day 100, respectively, with 23% (95%CI: 6–40) having chronic GVHD at 1 year. Six month transplant-related mortality was 22% (95%CI: 5–39). With a median follow-up of 10 months (range: 3.5 months–2.5 yrs), disease-free survival (DFS) is 57% (95%CI: 35–79) at 1 year, with 72% (95%CI: 49–95) of patients alive at 1 year if transplanted in remission. These data clearly demonstrate the safety of double unit UCBT. Despite the low infused CD34+ cell dose of the predominating unit, all evaluable patients achieved sustained engraftment, with a low incidence of severe acute GVHD despite HLA-disparity. This has resulted in a low TRM, & DFS is high if patients are transplanted in remission. While the NC & CD34+ cell doses of each unit do not predict unit predominance, these parameters in the predominating unit determine the speed of neutrophil recovery. As a suitable double unit graft can be identified for the majority of adults, this approach represents a major extension of access to HSC transplantation.

Steroid Refractory Acute and Chronic Graft Versus Host Disease (GVHD) - Response to Photophoresis+/− Rituximab.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5358-5358 ◽  
Author(s):  
Ramakrishnan Parameswaran ◽  
Maggie Sekeramayi ◽  
Kelly McCaul ◽  
Bill Bradfeldt
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Bk Virus ◽  
High Dose ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Gi Tract ◽  
Steroid Refractory

Abstract Acute GVHD is an important complication following hematopoeitic stem cell transplantation (HSCT), with significant attendant morbidity and mortality. High dose steroids remain the cornerstone of therapy. Steroid refractory GVHD carries a very poor prognosis. Various therapies are available for steroid refractory acute GVHD, but response is not uniform. Among the less intensive regimens, extracorporeal photopheresis (ECP) and rituximab, a chimeric humanized anti CD 20 monoclonal antibody have been shown to be useful in treating refractory acute and chronic GVHD. We describe 8 patients who developed GVHD following transplantation of HLA-identical stem cells, from siblings in 7 and from an unrelated donor in one. 2 patients had steroid refractory chronic GVHD of the liver, 3 patients had a refractory chronic GVHD of the skin and one had a steroid responsive restrictive pulmonary syndrome. Of the patients with skin GVHD, 2 had chronic scelrodermatous GVHD, which was of 20 years duration in one patient and 8 in the other. 2 patients had acute GVHD of the GI tract. The age range was 21– 53 years. All patients were in complete remission from their primary disease at the time of therapy for GVHD. 3 patients had a diagnosis of acute lymphoblasitc leukemia and 5 acute myeloid leukemia All had failed treatment with high dose steroids and/or tacrolimus and/or cellcept, and, one had also failed ATG therapy. Then therapy for refractory GVHD was initiated with rituximab in 3 patients and with photopheresis in 5. 7 patients received ECP. One patient with refractory chronic GVHD of the liver received rituximab alone in addition of steroids and tacrolimus. The patients with acute GVHD were treated with daily ECP for 10 days and then were weaned down to two procedures every 2 weeks. Patients with chronic GVHD received ECP 2 to 3 times a week for 6 weeks and were subsequently similarly weaned down. In the patients with acute GVHD of the GI tract complete responses occurred at 10 days in one patient and 45 days in the second as determined by complete cessation of diarrhea, cramps and nausea. Both patients with chronic GVHD of the liver achieved normalization of the serum bilirubin by 26 and 38 days after initiation of therapy. All patients tolerated successful taper of steroid therapy. The two patients with sclerodermatous GVHD have shown marked improvement in skin texture and range of motion at the involved joints. The patient with the pulmonary symptoms has shown complete normalization of pulmonary function. 5 patients were at risk of CMV reactivation, but failed to do so. One patient developed BK virus associated hemorrhagic cystitis that required therapy with cidofovir. There were 3 admissions for neutropenic fever, three for pneumonia and one each for gastroenteritis, HSV gingivostomatitis and line related sepsis. Two patients had line related thrombosis. None of the patients had relapse of their disease. 2 of the responders had an ECOG performance status 2, two of 3, one of 4 and four of &lt;/= 1 while being treated. All patients demonstrated improvement in functional status. ECP and rituximab is a well tolerated and effective modality for therapy of steroid refractory chronic and acute GVHD in both related and unrelated marrow stem cell transplant recipients.

Reduced Intensity Conditioning (RIC) with Cladribine, Busulfan and 4 Gy Total Body Irradiation (TBI) for Bone Marrow Transplantation (BMT) from an HLA-Matched Unrelated Donor (URD): A Prospective Multi-Institutional Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5397-5397 ◽  
Author(s):  
Sung-Won Kim ◽  
Masayuki Hino ◽  
Kazuo Hatanaka ◽  
Yasunori Ueda ◽  
Ryuji Tanosaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
High Response Rate ◽  
High Dose ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract [Background] We report the results of a prospective multi-institutional clinical trial of BMT from an HLA-matched URD following RIC. [Patients and Methods] The conditioning regimen included cladribine 0.11 mg/kg on day -8 to day -3, busulfan 4 mg/kg po on day -6 and day -5, and 4 Gy TBI on day -1. GVHD prophylaxis included cyclosporine and short-term methotrexate. Patients with hematologic diseases were eligible for this study if they were either older than 50 years or had significant medical contraindications to undergo conventional transplantation. Primary endpoints were neutrophil engraftment and achievement of complete donor-type chimerism (CD3+ cells >90%) on day 90. Regimen-related toxicities (RRT) between day -8 and day 28 were assessed by the NCI-CTC v2.0. A total of 27 patients were registered, but one patient was removed before transplant because of severe fungal infection. [Results] The median follow-up time was 722 days (range, 324–996) among survivors. The median age of patients was 56.5 years (36–64). Nine of the 26 patients (36%) had advanced-stage diseases and 3 (11%) had failed previous high-dose autologous or allogeneic transplantation. The diagnoses included AML (n=9), MDS/MPD (n=7), NHL (n=3), ALL (n=2), CML, ATLL, PCL, biphenotypic acute leukemia, and severe aplastic anemia (n=1). The median number of infused nucleated cells was 2.2 × 108/kg. After transplant, while one patient experienced engraftment failure and subsequent sepsis, and died on day 34, the remaining 25 patients achieved neutrophil engraftment (median, 17th day). Another patient was censored from the study due to grade 4 liver dysfunction, which developed on day 19, which left 24 patients for the chimerism analysis. The percentage of donor chimerism in CD3+ cells on days 28, 56 and 90 was, respectively, 88% (21/24), 100% (24/24) and 100% (24/24). Grade 3 RRT included arrhythmia (n=1), hypoxia (n=3), hyperbilirubinemia or hypertransaminasemia (n=7), stomatitis (n=18) and diarrhea (n=4), and grade 4 RRT included hypoxia (n=1) and hyperbilirubinemia (n=1). Acute GVHD of grade II, III and IV occurred in 27%, 27% and 4%, respectively. Ten of 15 evaluable patients (67%) had extensive chronic GVHD. CMV reactivation occurred in 23 patients (89%); 4 had histologically confirmed CMV colitis, 1 had CMV pneumonitis and 1 had CMV hepatitis, while the remaining patients had asymptomatic viremia. Of the 16 patients with measurable disease at the time of BMT, 15 achieved complete remission. The 100-day and 1-year cumulative incidences of non-relapse mortality (NRM) estimated by the Kaplan-Meier method were 20% and 54%, respectively. The cause of death that contributed to NRM was infection, with grade 0–I acute GVHD in 29% and grade II–IV acute GVHD in 71%. The 100-day and 1-year cumulative incidences of relapse were 8% and 35%, respectively, and the 1-year overall and progression-free survival rates were 42% and 30%, respectively. [Conclusions] The results support the feasibility of this procedure with a high response rate, but there is still a problem with the high NRM due to uncontrollable infections primarily associated with GVHD.

Unrelated Cord Blood Transplantation Using Myeloablative Regimen for Acute Leukemia Patients Aged between 50 and 55 Years: Single Institutional Retrospective Comparison with Patients Less Than 50 Years of Age.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2013-2013
Author(s):  
Takaaki Konuma ◽  
Satoshi Takahashi ◽  
Jun Ooi ◽  
Akira Tomonari ◽  
Nobuhiro Tsukada ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cord Blood ◽  
Older Patients ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Age Groups ◽  
Younger Patients ◽  
Cell Dose ◽  
Significant Difference

Abstract Background: Increasing age has been well-known as an obvious risk factor for graft-versus-host disease (GVHD) and transplant-related mortality (TRM) resulting negative impact on allogeneic transplantation including cord blood transplant (CBT). The incidence of sever GVHD after CBT, on the other hand, is lower than that after transplants using graft from adult cells, so we have expected the better results of CBT in older patients. Objectives and Methods: This study aimed to evaluate safety and efficacy of CBT using myeloablative regimen for older patients with acute leukemia. Patients and Methods: We retrospectively compared outcomes of older patients with acute leukemia with younger adults in our institute. Nineteen elderly patients (median age 52, range 50–55) and 81 young patients (median 49, range 16–49) received myeloablative conditioning regimen including 12 Gy of total body irradiation. GVHD prophylaxis comprised cyclosporine with (N=96) or without (N=4) methotrexate. Results: Comparisons of characteristics in the 2 age groups showed similar distributions for weight, gender ratio, diagnosis [de novo acute myeloid leukemia (AML), myelodysplastic syndrome related secondary AML, or acute lymphoblastic leukemia], disease status at transplantation, total nucleated cell dose and CD34+ cell dose in the graft before cryopreservation and proportions of HLA and sex compatibility between donors and recipients. The median period of follow-up for survivors after CBT was 730 days for older group and 1331 days for younger group, respectively. Grade II to IV acute GVHD occurred in 10 of 17 evaluable older patients and 49 of 75 evaluable younger patients (P = 0.61), while no older patients, but 6 younger patients developed grade III to IV acute GVHD. Extensive-type chronic GVHD occurred in 4 of 15 evaluable older patients and 18 of 69 evaluable younger patients (P = 0.96), respectively. The cumulative incidence of TRM at 100 days was 5% versus 6% (P = 0.70), and of relapse at 3 years was 29% versus 20% (P = 0.33) and the estimated disease-free survival at 3 years was 67% and 71% (P = 0.53) for older or younger patients, respectively. There was no significant difference in GVHD, TRM, relapse, and DFS between 2 age groups. Conclusion: The use of cord blood as a stem cell source might contribute to be decreased in the incidence of acute and chronic GVHD resulting in decreased TRM in older patients. Our results suggest that myeloablative CBT might be as safe and effective in patients with acute leukemia aged between 50 and 55 years as in younger patients.

Sustained Graft-Versus-Lymphoma Effect among Patients (pts) with Mantle Cell Lymphoma (MCL) Given Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2147-2147 ◽  
Author(s):  
Mohamed L. Sorror ◽  
Barry Storer ◽  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
Thomas Chauncey ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Median Number ◽  
Therapeutic Modality ◽  
High Dose ◽  
Duration Of Treatment ◽  
Autologous Hct

Abstract We previously reported 2-year overall survival (OS) of 65% among 33 pts with MCL given nonmyeloablative HCT (Blood2004; 104: 3535). Here, we update our results on the initial 33 pts with median follow up of 63 months and report on 20 additional pts with emphasis on: long-term disease control and resolution of chronic GVHD. Pts were conditioned with 2Gy TBI with or without fludarabine (90 mg/m2). Median age for all pts was 56 (range 33–75) years and median number of prior regimens was 4. Forty percent of pts had failed high-dose autologous HCT and an additional 11% had planned autologous HCT before allograft (4 pts had refractory disease and 2 were in PR). Comorbidity scores of ≥3 were found among 40% of pts. Forty percent of pts were not in CR/PR at HCT and 26% and 21% had marrow infiltration and lymph node size ≥5 cm, respectively. Donors were related (n=28) or unrelated (n=25). After HCT, incidences of grades II, III, and IV acute GVHD were 25%, 13%, and 9% respectively, and chronic extensive GVHD was 53%. Complete (CR) and partial remissions (PR) were seen in 71% and 3% of pts with measurable disease at HCT, respectively. Estimated 5-year rates of non-relapse mortality (NRM), progression/relapse, OS, and progression-free survival (PFS) were 27%, 22%, 58%, and 52%, respectively (Table 1). Among 19 pts in CR at HCT, 11 are alive and in CR, 7 died in CR, and one relapsed (now in CR after Rituximab and donor lymphocyte infusion). Among 13 in PR at HCT, 10 achieved CR and are alive, one died in PR, and 2 died from relapse. Among 21 pts with refractory/relapsed disease at HCT, 12 achieved CR and are alive, 2 have stable disease and are alive, and 7 relapsed (2 are alive in CR and PR after further treatment). At 5-years, 44% and 14% were alive without or with chronic GVHD requiring immunosuppression (Figure); and median duration of treatment for chronic GVHD was 33 months. Outcomes were comparable among related and unrelated recipients. Relapse rates were 47% vs. 14% among pts with vs. without LN size of ≥5 cm (p=0.02) and NRM was 41% vs.17% (p=0.05) among pts with HCT-CI scores of ≥3 vs. 0–2, respectively. Nonmyeloablative HCT is a potentially curative therapeutic modality for pts with advanced MCL, including patients who were chemotherapy-refractory, with a median PFS beyond 5 years. Sustained remissions and continuing resolution of chronic GVHD were observed with extended follow up. Pts with bulky LN might benefit from further debulking strategies before HCT. Table: Outcomes by donor type Donor Related (n = 28) Unrelated (n = 25) % % Grades III–IV non-hematological toxicities 39/18 38/26 Acute GVHD, grades II/ III/ IV 22/14/7 28/12/12 Chronic GVHD 50 55 CR 73 67 5-year NRM 26 28 5-year Progression/relapse 22 21 5-year PFS 53 51 5-year OS 59 56 5-year Pts alive with chronic GVHD requiring immunosuppression 14 7 Figure Figure

Graft-Versus-Tumor Effect In Patients with Graft-Versus-Host Disease Defined by NIH Consensus Criteria

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2343-2343
Author(s):  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
Seung-Ah Yahng ◽  
Ki-Seong Eom ◽  
Yoo-Jin Kim ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Proportional Hazards ◽  
Chronic Gvhd ◽  
Onset Time ◽  
Cox Proportional Hazards ◽  
Time Dependent ◽  
Survival Outcomes ◽  
Proportional Hazards Regression ◽  
Short Course ◽  
Unrelated Donors

Abstract Abstract 2343 Background. The National Institutes of Health consensus criteria (NCC) for chronic graft-versus-host disease (GVHD) are based on clinical manifestations rather than onset time after transplantation. Previous studies about the feasibility of the new criteria have been performed in patients who survived beyond 100 days after transplantation and had GVHD presenting after day 100. In order to investigate and compare the clinical impact of acute and chronic GVHD by NCC on survival, a cohort including patients with GVHD presenting ‘before' as well as ‘after' day 100 is needed. Additionally, a proper statistical tool should be applied to clarify the effect of GVHD on survival outcomes, because the occurrence of GVHD is a well known time-dependent event. In this context, we examined a cohort including all patients who underwent allogeneic stem cell transplantation (SCT) in order to investigate clinical impact of acute or chronic GVHD by NCC on survival outcomes. Methods. We retrospectively investigated 771 patients who underwent allogeneic SCT between January 2002 to December 2008. To study a homogenous cohort, patients received 2 allogeneic SCT and/or donor-lymphocyte-infusion was excluded. We used time-dependent analyses to reveal the effect of GVHD on survival outcomes. In particular, to approach the effects of GVHD as a time-dependent covariate on competing risks [relapse or transplant-related mortality (TRM)], we analyzed cause-specific hazards by Cox proportional hazards regression model (Cartese G, Andersen PK. Biometrical Journal 2009;51:138–158). Results. The median age was 36 years (range, 15–68). Patients had various hematologic malignancies (AML/ALL/CML/MDS/MM, 361/226/86/67/31, respectively) and were transplanted from matched sibling (n=485), well-matched unrelated donors (n=154), partially-matched unrelated donors (n=101), and mismatched unrelated donors (n=31). Conditioning regimens consisted of myeloablative (n=536) and reduced-intensity regimens (n=235). GVHD prophylaxis consisted of cyclosporine and short-course methotrexate for related SCT and tacrolimus and short-course methotrexate for unrelated SCT. Among 771 patients, 540 patients were diagnosed with GVHD after transplantation. According to onset time of GVHD, in 348 patients GVHD developed within 100 days after SCT, whereas in 156 patients GVHD occurred more than 100 days after SCT. Using the NCC, we classified patients as three categories regardless of onset time: (1) acute GVHD (n=215), if patients had only acute features (no chronic features) during the course of GVHD, (2) acute GVHD with following chronic GVHD (n=118), if patients had any chronic features after the occurrence of acute GVHD, and (3) chronic GVHD (n=207), if patients had any chronic features at the onset of GVHD. Multivariate analyses using cause-specific hazards revealed that acute GVHD was significantly associated with lower relapse incidence [HR (95% CI) 0.65 (0.44–0.94), P=0.023]. However, it did not influence disease-free survival (DFS, P=0.602) and overall survival (OS, P=0.294) due to higher TRM in patients with acute GVHD [HR (95% CI) 1.74 (1.15–2.61), P=0.008]. Acute GVHD with following chronic GVHD was also associated with lower relapse incidence [HR (95% CI) 0.31 (0.15–0.66), P=0.002] and higher TRM [HR (95% CI) 2.89 (1.65–5.04), P<0.001], which did not influence DFS (P=0.567) and OS (P=0.820). On the other hand, the occurrence of chronic GVHD significantly reduced relapse rates [HR (95% CI) 0.46 (0.29–0.75), P=0.002] without increasing TRM (P=0.177). Indeed, this effect was translated into improved DFS [HR (95% CI) 0.67 (0.48–0.95), P=0.023]. Conclusions. Our data show that both acute and chronic GVHD by NCC reduced the risk of relapse, demonstrating the presence of graft-versus-tumor (GVT) effect by the occurrence of GVHD and no difference according to the clinical features (acute or chronic) by NCC. However, survival benefit was only observed in chronic GVHD by NCC compared to acute GVHD with/without following chronic GVHD by NCC due to higher TRM. This study represents the first one demonstrating the GVT effect of GVHD defined by NCC in a cohort including GVHD presenting ‘before' as well as ‘after' day 100 using appropriate time-dependent analyses by cause-specific hazards by Cox proportional hazards regression model. Disclosures: No relevant conflicts of interest to declare.

High-Dose Rituximab in the Conditioning Regimen Before Allogeneic Stem Cell Transplantation Reduces the Incidence of Acute Gvhd in B-Cell Lymphomas

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4546-4546
Author(s):  
Paolo Corradini ◽  
Barbara Sarina ◽  
Cristiana Carniti ◽  
Francesca Patriarca ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Unrelated Donors

Abstract Abstract 4546 Background: Reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed lymphomas. The present GITMO study is a prospective multicenter phase II trial for patients affected by relapsed CD20 positive lymphomas. Compared with the previous thiotepa/fludarabine/cyclophosphamide GITMO protocol (Leukemia 2007), the thiotepa dose is increased, and high-dose Rituximab is included in the regimen to improve the outcome and possibly modulate the incidence of acute GVHD. Aims: Primary end-point was 1-year progression-free survival; secondary endpoints were non-relapse mortality and incidence of acute and chronic GVHD. Methods: Fifty-seven patients (pts) were enrolled so far in the study and 49 are evaluable for analysis. Treatment plan consisted of high-dose R (500 mg/ms on day -6) followed by thiotepa (12 mg/kg), fludarabine (60 mg/kg) and cyclophosphamide (60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mini-methotrexate; ATG (7.5 mk/kg) was only added for pts allografted from one antigen mismatched sibling or unrelated donors. Histopathological subtypes included 24 aggressive (HG) (n= 17 diffuse large B-cell lymphomas, n= 7 mantle cell lymphomas) and 25 indolent lymphomas (LG) (n= 13 follicular lymphomas, n= 12 small lymphocytic/chronic lymphocytic leukemia). Patients were allografted from related siblings (SIB) (n= 32 matched, n=1 one single mismatched) or unrelated donors (UD) (n=11 matched, n=5 mismatched). All the pts had chemosensitive disease (n=20, 41% in complete remission) and 26 (53%) came from a failed autoSCT. Results: At a median follow-up of 13 months (range, 5–44 months), 36 pts are alive [n=27 (75%) in CR] and 13 died from any cause [n=6 for non-relapse mortality (NRM), n=7 for disease progression]. All the patients engrafted (94% had full donor chimerism at 3 months). The cumulative incidence (CI) of NRM was 13% at 1 year: 9% vs 19% for SIB and MUD (p=0.3), and 9% versus 16% for for LG and HG (p=0.3), respectively. In total only 11 of 49 pts had acute GVHD (n=8 grade II, n=3 grade III) with an estimated CI of 21% at 100 days. In the previous GITMO study the incidence was 35% with SIB only. Forty pts are evaluable for chronic GVHD with an estimated CI of 41% and 47% at 1 and 2 year, respectively (n=11 limited, n=3 extensive). Infections after engraftment requiring hospitalization or intravenous treatment were evaluable in 46 pts (n=3 excluded for early death). The overall incidence of infections was 58% (n=27) including 5 pts experienced sepsis and 10 pts pneumonia. Preliminary data on immune-reconstitution at 1 year showed: 1) low number of circulating B cells (median CD19+/ul: 129/ul) with an expansion of naive cells (IgD+, CD27-); 2) the median value of IgM was 89 mg/dl whereas IgG and IgA remained at low levels. The CI of relapse was 26% and 37% at 1 year and 2 years, respectively. In the indolent and aggressive groups, OS estimates at 2 years were 79% (95%CI, 52%-91%) and 61% (95 CI, 38%-77%) and PFS estimates were 53% (95%CI, 23%-76%) and 48% (95% CI, 27%-66%), respectively. Conclusions: The present data suggest that the administration of high-dose R is feasible and causes an unexpected reduction of the incidence of acute GVHD without increasing the NRM and the incidence of severe infections complications. Complete data evaluating the effects of R on immune reconstitution are ongoing. Disclosures: No relevant conflicts of interest to declare.

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