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.

Unrelated Cord Blood Transplantation (UCBT) for Transfusion- Dependent Thalassemia a CIBMTR Audited Retrospective Analysis of 30 Consecutive Patients from a Single Center

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 131-131 ◽  
Author(s):  
Tang-Her Jaing ◽  
Brian Wang ◽  
David Gjertson ◽  
Ping Law ◽  
Lawrence Petz ◽  
...  
Keyword(s):  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Young Patients ◽  
Disease Free Survival ◽  
Thalassemia Major ◽  
Clinical Results ◽  
Traumatic Head Injury ◽  
Cell Dose ◽  
Abo Incompatibility ◽  
Related Mortality

Abstract UCBT offers a cure for thalassemia and has advantages as a stem cell source because the requirement for an HLA match between donor and recipient is less stringent. Previous reports of UCBT for thalassemia have yielded transplant related mortality (TRM) that was quite high and it is known that pre-freeze total nucleated cell (TNC) dose is critical for UCBT. With strategies that maximize TNC dose – using non-red cell reduced but plasma depleted (PD) CB, no post-thaw wash (NW), and double cord transplantation (DCT) when necessary – we have achieved promising results with UCBT in young patients with transfusion-dependent β-thalassemia. Between 10/2003 and 5/2008, 39 CB products were infused after Bu/Cy/ATG myeloablation into 30 pediatric thalassemia major patients (9 DCT) using NW PD CB exclusively. Patient status: 21 Pesaro class−1, 8 Pesaro class−2, and 2 unknown. Median age was 5 years (range 1–14 years) with a median weight of 18 kg (range 11–37 kg). The data was audited by the transplant center (TC) and on-site by CIBMTR (98.5% accuracy for Chang Gung). Median pre-freeze TNC cell dose was 10.9×107/kg, and median pre-freeze CD34+ cell dose was 4.0×105/kg. The number of CB products HLA ABDR matched were 4, 11, and 24 for 6/6, 5/6, and 4/6 or fewer matches. No significant adverse events were observed despite major ABO incompatibility in some cases and forgoing post-thaw wash. Cumulative incidences of donor-derived (determined by chimerism studies) neutrophil (ANC500), platelet 20K and 50K (plt 20K & 50K) engraftment were 96±11%, 92±11% and 92±12%, and median times to ANC500, plt 20K and 50K engraftment were 17.5 days (range 11–26), 49.5 days (range 28–135) and 63.5 days (range 35–203), respectively. Grade III/IV acute GvHD occurred in 40±9%, and extensive chronic GvHD occurred in 4±4% of the patients. Transplant related mortality were 10±5% at 100 days and 13±6% at 1 year. Overall survival at 1 and 3 years were 87±6% and 82±8%, while disease-free survival at 1 and 3 years were 85±7% and 78±9%. Five patients expired including 1 death prior to day +10 due to traumatic head injury. Mean and median follow up times were 24 and 16 months respectively (range 0.3–58 months) as of August 2008. To our knowledge, this is the largest single-institutional UCBT series for thalassemia, and shows the favorable clinical results that are attainable when TNC dose is optimized with PD CBU, no post-thaw wash and DCT when necessary.

scholarly journals Day 45 Lymphocyte Recovery Is Independently Associated with Transplant-Related Mortality after Adult Myeloablative Double-Unit Cord Blood Transplantation (dCBT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1156-1156
Author(s):  
Duncan Purtill ◽  
Doris M. Ponce ◽  
Sean M. Devlin ◽  
Marissa N Lubin ◽  
Parastoo B Dahi ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Lymphocyte Count ◽  
Acute Gvhd ◽  
Univariate Analysis ◽  
Disease Stage ◽  
Neutrophil Recovery ◽  
Cell Dose ◽  
Recipient Age ◽  
Related Mortality ◽  
Neutrophil Engraftment

Abstract Background: Our center has reported that the infused viable CD34+ cell dose of the dominant unit determines the speed & success of neutrophil recovery after dCBT (Purtill et al, Blood 2014). However, how unit characteristics affect lymphocyte recovery has not been determined, & the effect of both delayed neutrophil & lymphocyte recoveries on transplant-related mortality (TRM) requires investigation. Methods: The association between 1) dominant unit characteristics (TNC, CD34+, CD3+ cell doses & 8-allele HLA-match) & lymphocyte recovery, & 2) the effect of both neutrophil & lymphocyte recoveries on TRM were analyzed in 98 adult myeloablative dCBT recipients (median age 42 years, range 16-69) transplanted for hematologic malignancies. The analysis was restricted to adults given the significant differences in patients (pts), grafts, & neutrophil recovery in children. Results: The cumulative incidence of day 45 neutrophil engraftment ≥ 0.5 x 109/L was 96% (95%CI:89-99) with a median recovery of 25 days (range 12-43). The day 45 cumulative incidence of lymphocyte engraftment ≥ 0.2 x 109/L was also 96% (95%CI:89-99, median 25 days, range 12-59). Dominant unit infused viable CD34+ cell dose determined both neutrophil (as previously reported) & also lymphocyte recovery. To analyze if the speed & success of neutrophil & lymphocyte recovery are important in determining subsequent TRM in engrafting pts, we performed a day 45 landmark analysis of the 93 patient subset who achieved neutrophil engraftment & were alive 45 days post-dCBT (5 pts with graft failure or early death were excluded). In univariate analysis, a trend toward increased day 45-180 TRM was observed among the 51 pts with delayed neutrophil engraftment > 25 days [HR 2.71 (95%CI 0.88-8.42), p = 0.084], but there was no association between the absolute neutrophil count on day 45 & subsequent TRM. Conversely, while the time to lymphocyte recovery ≥ 0.2 x 109/L was not significant, the day 45 lymphocyte count correlated significantly with day 45-180 TRM. A lymphocyte cut-point of 0.3 x 109/L was identified below which TRM risk was markedly increased: 17 dCBT recipients with a day 45 lymphocyte count < 0.2 had a TRM HR 12.04 (95%CI: 4.33-33.52), p < 0.001 (Figure). Age > 40 years & recipient CMV seropositivity were also associated with a trend toward increased day 45-180 TRM in univariate analysis whereas regimen intensity, disease status, & dominant unit HLA-match were not. Patient demographics (age, weight, disease stage, CMV serostatus, & conditioning intensity) & dominant unit characteristics (infused TNC, viable CD34+, CD3+ cell doses) were similar in pts with day 45 lymphocyte counts > or < 0.2 x 109/L. Low lymphocyte count < 0.2 x 109/L was not explained by differences in corticosteroid therapy. The causes of day 45-180 TRM in pts with low day 45 lymphocytes were organ failure (n = 5) & acute GVHD (n = 4) with one patient dying of infection. On multivariate analysis, day 45 lymphocyte count < 0.2 x 109/L was independently associated with a greater day 45-180 TRM risk (p < 0.001, Table) while a trend was observed for delayed neutrophil engraftment (p = 0.069). Recipient age > 40 years & CMV serostatus were not significant (p = 0.196 & p = 0.418, respectively). The relationship between lymphocyte recovery & TRM was maintained when the 20 pts on therapy for acute GVHD by day 45 were excluded. Conclusion: Both early neutrophil & lymphocyte recovery are critically important factors in the success of adult myeloablative dCBT. While it is well appreciated that early failure of neutrophil recovery is associated with a very high mortality rate, this analysis of pts engrafting with neutrophils suggests a low lymphocyte count (<0.2) at day 45 was associated with a high risk of early TRM and was an independent and more powerful TRM risk factor than the speed of prior neutrophil recovery. The exact mechanisms that underlie this observation require further investigation but these findings emphasize the importance of considering both neutrophil and lymphocyte recovery in the assessment of the quality of early CB engraftment. Table. Variable n HR (95%CI) p Speed of ANC recovery < 25 days 42 Reference 0.069 ≥ 25 days 51 2.94 (0.92-9.39) Lymphocyte count at day 45 > 0.2 x 109/L 76 Reference < 0.001 < 0.2 x 109/L 17 12.10 (4.21-34.81) * Recipient age and CMV serostatus were included in the initial model but removed using a backward conditional method. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Fludarabine and Busulfan (FluBuP Regimen) as Myeloablative Conditioning Regimen for Allogeneic PBSCT in 71 Leukemic Patients (A Unicenteric Study).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5156-5156
Author(s):  
Masoud Iravani ◽  
Maryam Tavakoli ◽  
Ahmad Reza Shamshiri ◽  
Mohammad Reza Evazi ◽  
Asadollah Mousavi ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Cmv Infection ◽  
Platelet Recovery ◽  
Low Incidence ◽  
Reduced Toxicity

Abstract Following 3 other centers in USA, Canada and Germany, we are evaluating fludarabine (40 mg/m2 on days −6 to −2) and busulfan (4 mg/kg/day on days −5 to −2) as a new conditioning regimen for allogeneic peripheral blood stem cell transplantation in leukemic patients with matched related donors. Seventy one patients were enrolled, 18 with high and 53 with standard risk (18 ALL, 35 AML, 16 CML and 2 MDS; F=29 M=42). The median patient age was 23.7 years(range, 2.4– 46.7). Cyclosporine was used as a prophylactic agent for GVHD (3mg/kg IV till +4, 10 mg/kg oral from day +5). The median follow-up was 269 days (range, 50–459 days). 91.5% and 15.5% developed mucositis and hepatic toxicity respectively which resolved with conservative therapy. There was no cardiac toxicity (except one patient with mild pericardial effusion and another with tachycardia). The median of highest serum creatinin level during hospitalization were 1.6 mg/dl (range, 0.8–3.7; 24.3% with Cr>2) and serum cyclosporine level, at the same time, was 246 ng/ml (range, 9–814). 7% experienced hemorrhagic cystitis (infection was ruled out) and 36.6% experienced moderate to severe headache. 38% and 14.1% of the patients showed grade 1, 2 and grade 3 acute GVHD respectively. Grade 4 acute GVHD was found in one patient. 50% and 6% showed limited and extensive chronic GVHD. 27% of patients became CMV+ (min +17, max +69). The median time for neutrophil and platelet recovery were 10 (min 0, max +26) and 12 (min 0, max +30) days. In day +38, 86.7% of the patients had 90% or more, mononuclear chimerism (with STR-PCR technique; median, 97%; range, 25–100). 5 ALL and 8 AML patients relapsed (18.3% of all patients) and 6 (8.45%) died after relapse. Nonrelapse mortality was 13% (9 patients; acute GVHD grade IV=1, CMV infection and GVHD=2, CMV infection=2, pneumonia=2, infection=2). With a median follow up of 9 months (range, 1.6–15.3 months), the probability of overall survival and disease free survival were 79.68% and 81.26% respectively. It could be beneficial to use fludarabine versus cyclophosphamide in standard conditioning regimen for leukemic patients because of reduced toxicity, low incidence of acute GVHD and facilitated donor engraftment.

Analysis of 120 Pediatric Patients with Non-Malignant Disorders Transplanted Using Unrelated Plasma Depleted Cord Blood and the Role of Post-Thaw Wash

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4406-4406
Author(s):  
Joseph Rosenthal ◽  
Tang-Her Jaing ◽  
Lee Lee Chan ◽  
Gretchen Eames ◽  
Michael L. Graham ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cord Blood ◽  
Cumulative Incidence ◽  
Pediatric Patients ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Free Survival ◽  
Disease Free ◽  
Related Mortality

Abstract Unrelated cord blood (UCB) is an important stem cell source for unrelated hematopoietic cell transplantation of patients with non-malignant disorders. Cell dosage is a critical factor for successful UCB hematopoietic stem cell transplantation (HSCT). The red cell reduced (RCR) and post-thaw wash techniques that are widely used incur significant nucleated cell loss. Three strategies were employed to maximize cell dose and improve outcome–use of cord blood processed with plasma depletion without red blood cell reduction (PD CB), avoidance of post-thaw wash, and the use of double cords (2X) when necessary. A CIBMTR-audited analysis was performed on all 120 pediatric patients with non-malignant disorders transplanted with PD CB at 29 U.S. and 17 international centers. Transplant characteristics: median age 3.5 years (range 0.1–14); median patient weight 15 kg (range 4–61); male 58%. The majority of patients (n=58; 55%) were Asian. Twenty-two (21%) patients were Hispanic, 15 (14%) were Caucasian, 6 (6%) were African-American, and three (3%) were of Middle Eastern background. HLA ABDR matches: 6/6–26; 5/6–48; 4/6–47; 3/6 or 2/6–6; median pre-freeze nucleated cell dose 10.5×107/kg; median pre-freeze CD34+ dose 3.7×105/kg; non-myeloablative regimen 24%; 58% infused without post-thaw wash (NW). Myeloid engraftment defined as ANC≥500 and 6-month platelet engraftment defined as ≥ 20K and ≥ 50K are 89±8%, 88±8%, and 84±6% respectively. The median time to myeloid and platelet engraftment are 21 days (range 11–64), 49 days (range 13–155), and 61.5 days (range 21–205) respectively. No major adverse event was observed in either the W or the NW group. The cumulative incidence of reported grade II–IV acute GVHD was 38±5%, and 19±4% had grade III–IV acute GVHD. 36±6% developed limited chronic GVHD, and 12±4% developed extensive chronic GVHD. With a median follow-up of 329 days (range 3–1928 days), the Kaplan-Meier estimates of 1-year TRM, OS and diseasefree survival were 20±6%, 88±6% and 72±6% respectively. Foregoing post-thaw wash for PD CB transplantation improved neutrophil (RR=1.75; p=0.01) and platelet engraftment (RR=1.72; p=0.02) and reduced TRM (RR=0.38; p=0.04). This series demonstrated that unrelated PD CB transplantation can be performed safely and effectively in children with life-threatening, non-malignant disorders. Additionally, the results demonstrate possible improvement in myeloid and platelet engraftment, overall and disease-free survival when post-thaw wash is not employed. Table 1. Summary of overall results Outcome All Patients N = 120 Washed CB N = 48 Unwashed CB N = 71 RR (Wash=Ref) P-value ANC500 Engraftment Cumulative Incidence Median # Days to Engraftment 87±6% d+21 86±9% d+25 89±8% d+19 1.75 0.01 Platelet 20K Engraftment Cumulative Incidence Median # Days to Engraftment 81±6% d+49 75±9% d+52 88±9% d+43 1.72 0.02 Autologous Recovery 3±2% 2±2% 4±3% 1.06 0.95 Acute GvHD II–IV Acute GvHD III–IV 38±5% 19±4% 31±7% 17±6% 45±7% 21±6% 1.74 1.38 0.11 0.50 Chronic GvHD Limited Chronic GvHD Extensive 36±6% 12±4% 14±6% 19±6% 60±10% 6±4% 5.69 0.24 &lt;0.001 0.08 Transplant-Related Mortality–100 Day Transplant-Related Mortality–3 Yr 10±3% 20±4% 11±5% 34±8% 9±4% 11±4% 0.38 0.04 Overall Survival–1 Yr Overall Survival–3 Yr 79±4% 79±4% 66±8% 66±8% 88±4% 88±4% 0.43 0.06 Disease-Free Survival–1 Yr Disease-Free Survival–3 Yr 72±5% 70±6% 58±9% 51±10% 84±5% 84±5% 0.48 0.07

Adult Matched Sibling Blood Cell Transplants (BCT) after Myeloablative Conditioning Incorporating Daily Intravenous (IV) Busulfan (BU) and Low-Dose Antithymocyte Globulin (ATG): Outcomes with Particular Respect to Transplant-Related Mortality (TRM) in 140 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2313-2313
Author(s):  
James A. Russell ◽  
Ahsan M. Chaudhy ◽  
Oluyeme Jeje ◽  
Diana Quinlan ◽  
Douglas Stewart ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Low Dose ◽  
Acute Gvhd ◽  
Myocardial Infarct ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Increase Risk ◽  
Cell Transplants ◽  
One Year ◽  
Related Mortality

Abstract Intravenous BU allows more predictable exposure and is more convenient to administer once daily than the conventional four times daily regimen. Low-dose pretransplant ATG may reduce morbidity and mortality from graft-versus-host disease (GVHD). We have investigated a myeloablative regimen incorporating these agents in 140 adults aged 18–65 (median 47) receiving a first MRD SCT between 05/99 and 01/04. Conditioning comprised fludarabine (FLU) 50mg/m2on days −6 to −2 and IV BU (Busulfex, ESP Pharma) 3.2 mg/kg daily days −5 to −2 inclusive (FLUBUP) in 116 patients (pts) with additional TBI 200cGy x 2 in 24 (14 ALL, 8AML, 2 biphenotypic). Forty-three pts had standard-risk (SR) acute leukemia in CR1 (35 AML, 8 ALL), and 23 had active acute leukemia (HA) (18 AML±MDS, 3 ALL, 2 biphenotypic). A third group of 74 other (OTH) pts comprised 2 AML CR2, 2 ALL CR2, 2 CML (1 AP, 1CP2), 13 MDS, 11 MM, 24 NHL, 6 HD (2 with CLL), 8 CLL, 5 other. All pts were given cyclosporine A, “short course” methotrexate with folinic acid and Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Followup of survivors is 6–61 months, median 26. Incidence of acute GVHD (aGVHD) grade II–IV was 19±4%, grade III–IV 6±2% and chronic GVHD (cGVHD) 66±5% (at 2 years). Projected TRM is 4±2% at 100 days, 10±3% at 1 year and 14±4% at 5 years. For acute leukemia pts projected TRM at one year is 5±5% vs 12±5% with (n = 24) and without (n = 47) TBI respectively (p = ns). Four non-relapse deaths occurred before day 100 one each from myocardial infarct (MI), acute GVHD, candidiasis and VOD. Ten deaths between days 102–569 were related to aGVHD in one and complications in pts with cGVHD in 9 (occurring in 1 pt after 2nd BCT for graft failure) including 1 VZV, 3 other infection, 1 PE, 1 MI. Of 11 follicular NHL pts 3 died of cGVHD and its complications after 1st BCT compared with 5 of 129 others (p = 0.02). Twelve of the transplant-related deaths were in 76 pts ≥ 46 years old compared with 2 in 64 younger pts (TRM = 23±6%, vs 4±3%, p = 0.01). Of 55 relapsed pts 17 are alive, 8 of these are in remission after more treatment and/or onset of GVHD. Projected 5-year disease-free survival and survival respectively is 46±5% and 57±5% for all pts, 62±8% and 76±7% for SR, 51±7% and 59±9% for OTH, and 9±6% and 16±8% for HA. This study indicates that: 1) regimen related mortality is low in MRD BCT recipients given this regimen 2) cGVHD is the main cause of TRM 3) pts with follicular NHL seem to be comparatively susceptible to death related to cGVHD 4) addition of 400cGy TBI does not increase risk of TRM and 5) older age remains a risk factor for TRM.

Double Cord Blood Transplantation in Hematologic Malignancy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4426-4426
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Xingbing Wang ◽  
Liangquan Geng ◽  
Miao Zhou ◽  
...  
Keyword(s):  
Cord Blood ◽  
Median Time ◽  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Cord Blood Transplantation ◽  
Major Barrier ◽  
Promising Alternative ◽  
Cell Dose ◽  
Blood Transplantation ◽  
Cd34 Cells

Abstract Purpose: Cord blood transplantation (CBT) is a promising alternative means of allogeneic stem cell transplantation. However, the limited cell dose of single umbilical cord blood (UCB) unit has been a major barrier to its more widespread use. With the hypothesis that double CBT (dCBT) could circumvent the cell dose problem, we analyzed the early engraftment kinetics in 10 hematologic malignancy patients given 2 partially matched dCBT. Methods: Patients were eligible for dCBT when a single 4-6/6 HLAmatched UCB unit with adequate nucleated cell dose is unavailable. From November 2005 to June 2008, 10 patients (3 male and 7 female) with a median age of 22 years (range 10–37) and a median weight of 55kg (range 31–70 kg) were recruited, including 4 ALL, 3 AML, and 3 CML. All patients received myeloablative conditioning (Flu/Cy/TBI for 6 patients, BU/CY2 for 2 and BU/CY2/BCNU for one). Graft versus host disease (GVHD) prophylaxis was CSA+MMF. They received two units with at least one 5/6 HLA-match unit. The median combined graft nucleated cell (NC) dose was 3.98°Á107/kg (range 3.51–7.70°Á107 NC/kg), and the median CD34+ cell dose was 2.37°Á105/Kg (range, 0.94–5.23°Á105/kg). Results: Eight patients (80%) had sustained hematopoietiec recovery. The median time to an absolute neutrophils count &gt; 500 was 18 days (14'C29) and the median time to a platelet count &gt; 20,000 was 34 days (27–46). Among those patients, one displayed the engraftment derived from both donors for six months until her death. The both units were 6/6 HLA matched the recipient, and had similar number of nucleated cells, CD34+ cells and CD3+ cells. The sustained hematopoiesis was derived from a single dominant one in the remianing 7 pateints. By STR-PCR, the median values of the percentage of the dominant unit was 80%(30–100%)at post-transplantatiom day 7, and they all achieve complete donor chimerism at day 28. The median infused cell dose of the predominating unit was 2.6°Á107 NC/Kg (range 1.3–4.45 °Á107/kg), 1.56°Á105 CD34+/Kg, (range 0.47–4.00°Á105/kg), and 0.53°Á107CD3+/Kg (range 0.34–2.59°Á107/kg), in contrast to 1.46°Á107 NC/Kg (range 0.96–6.09°Á107/kg), 0.87°Á105CD34+/Kg (range 0.20–2.55°Á105/kg), and 0.52°Á107CD3+/Kg (range 0.12–1.69°Á107/kg) in the nonsustained unit. When analyzed separately, units with high numbers of total nucleated cells, CD34+ cells or CD3+ cells dominate the engraftments in 4 partially overlapping patients. Only 3 of the 7 patients with donor engraftment received 2 UCB units with different degrees of HLA disparity. Of these, the better HLA-matched unit to the recipient predominated in 1 patients, while lesser matched units engrafted over the better matched units in 2 patients. Acute GVHD grade = 1 \* ROMAN ICIII was scored in 3 patients (37.5%) (1 grade = 1 \* ROMAN I, 1 grade II and 1 grade III). No patients presented acute GVHD grade IV. Three patients died (2 fungal infection, 1 serious hepatitis). Conclusions: Two units CBT is a safe and effective alternative option for hematologic malignancy treatment. Generally, hematopoiesis will be dominated by only one unit in patient received dCBT and it may occur as early as 7days after transplantation. However, the mechanism to determine this dominancy remains elusive, as nucleated cell dose, CD34+ cell dose, CD3+ graft cell dose and HLA match all failed to predict the predominant unit. Table 1 Characteistics of dominant and non-dominant cord blood units patients No1 No2 No3 No4 No5 No6 No7 TNC (°Á107/Kg) Dominant unit 1.3 2.7 3.79 2.6 4.45 2.3 2.48 Non-dominant unit 2.3 1.3 3.7 1.3 6.09 0.96 1.46 CD34 (°Á105/Kg) Dominant unit 1.56 0.77 1.82 1.85 4 0.74 0.47 Non-dominant unit 1.16 1.45 2.55 0.25 0.87 0.2 0.83 CD3 (°Á107/Kg) Dominant unit 0.53 0.34 0.74 2.59 0.35 0.42 0.83 Non-dominant unit 0.4 0.12 0.56 1.69 0.52 0.49 0.96 HLA mismatch Dominant unit 1/6 1/6 0/6 1/6 1/6 1/6 1/6

Non-Myeloablative (NMA) Umbilical Cord Blood Transplantation (UCBT): Promising Disease-Free Survival in 95 Consecutive Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 559-559 ◽  
Author(s):  
Claudio G. Brunstein ◽  
Juliet N. Barker ◽  
Todd E. DeFor ◽  
Kathy French ◽  
Daniel J. Weisdorf ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Neutrophil Recovery ◽  
Autologous Transplant ◽  
Cell Dose ◽  
Related Mortality

Abstract Conventional allogeneic hematopoietic stem cell transplantation (HSCT) is limited by lack of rapidly available HLA-matched donors and excess transplant-related mortality (TRM). Therefore, we investigated the use of unrelated UCBT after NMA conditioning in patients (pts) with high-risk hematologic malignancy. From 10/01 to 06/05, 95 consecutive adults [median age 50 yrs (range 18-69), median weight 78 kg (range 50-134)] received a NMA prior to UCBT. Pts were eligible if aged &gt;45 yrs (n=70; 74%), or had extensive prior therapy (n=25; 26% with 17 having had a prior autologous HSCT). Therapy consisted of cyclophosphamide (50 mg/kg), fludarabine (200 mg/m2) and TBI (200 cGy), with cyclosporine A and mycophenolate mofetil immune prophylaxis. Thirty pts (32%) without prior autologous transplant or chemotherapy in the last 3 months also received anti-thymocyte globulin (ATG). Pts received one (n=17) or two (n=78) 4–6/6 HLA A,B, and DRB1 matched UCB units (109 units were 4/6, 53 were 5/6, and 11 were 6/6 HLA matched with the pt) with a median infused cell dose of 3.6 x 107 NC/kg (range 1.1–6.8). Units were 4–5/6 HLA matched to each other in instances of double UCBT. Four pts died prior to day 28. Median follow-up is 14 mos. (range 3.3–42.7). Median time to neutrophil recovery after UCBT was 12 days (range 0–32) with an incidence of sustained donor engraftment of 87% (95%CI: 80–94). Complete chimerism was achieved by day 100 in 96% of pts. Graft failure occurred in 11 (6 primary, 5 secondary), with autologous recovery in 8. In univariate analysis neither the number of donor units, age, disease risk, ATG in the preparative regimen, CMV serostatus, HLA matching, in the 3 months prior to transplant, CD34 cell dose, diagnosis, and prior autologous transplant were independent predictors of sustained donor engraftment. Multivariate analysis identified no independent predictors of sustained engraftment. Incidence of grade II-IV & III-IV acute GVHD at day 100 and chronic GVHD at 1 yr were 61% (95%CI: 49–73), 25% (95%CI: 14–36) and 25% (95%CI: 15–35), respectively. Incidence of acute GVHD was lower among recipients receiving of ATG, but the difference was not statistically significant (II-IV=46% vs. 68%, p=.19; III-IV=13% vs. 27%, p=.24). Incidence of treatment related mortality (TRM) at day 180 and relapse/disease progression at 2 years was 18% (95%CI: 10–26) and 32% (95%CI: 22–42), respectively. In multivariate analysis, only age &gt; 45 yrs (RR 0.3; 95%CI: 0.1–0.9, p=.03) and no chemotherapy within the 3 months prior to transplant were independent predictors of lower TRM (RR 0.36; 95%CI: 0.13–1.0, p=.05). Overall and progression-free survival were 52% (95%CI: 39–65) and 46% (95%CI: 35–57) at 1 yr, and 44% (95%CI: 30–58) and 43% (95%CI: 31–55) at 2 yrs, respectively. In Cox regression, age &gt;45 yrs (RR of death 0.5; 95%CI: 0.2–0.9, p=.02) and chemotherapy in the 3 months prior to transplant was associated with improved survival (RR of death 0.53; 95%CI: 0.28–1.0, p=.05). In summary, with our graft selection strategy, a NMA UCBT is readily available for &gt;90% of patients. NMA UCBT is associated with low TRM, and prompt neutrophil recovery, with progression free survival rates comparable to reported studies with HLA matched unrelated marrow HSCT. In the largest US series to date, these data suggest that age is not a limitation to allogeneic HSCT using UCB, in particular if it is the only reason for the patient to undergo a NMA transplant.

scholarly journals Investigating the Relationship between CD34+and CD3+ Cell Doses, One-Year Graft-Versus-Relapse-Free-Survival, Graft-Versus-Host Disease, and Overall Survival in Haploidentical Hematopoietic Stem Cell Transplantation: A Single Center Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2051-2051 ◽  
Author(s):  
Mindy Hsiao ◽  
Anastasia Martynova ◽  
George Yaghmour ◽  
Chris Foss
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Optimal Dose ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Improved Outcomes ◽  
The Mean ◽  
Related Mortality

Background: Haploidentical hematopoietic cell transplantation (haplo-HCT) has emerged as a popular alternative to traditional HLA-matched hematopoietic cell transplant. As the number of haplo-HCT's rises, investigating the factors that may affect outcomes is necessary in order to improve overall survival and reduce transplant-related mortality. The optimal dose of CD34+ cells used during haplo-HCT to ensure favorable outcomes using PTCy has not yet been reported though a range of 2 to 5.00x106 cells/kg is commonly used.Furthermore, the optimal dose of CD3+ cells is unknown however recent data has suggested less than 3.00x108 cells/kg may prevent the development of acute GVHD. The importance of studying the impact of CD34+/CD3+ cell dosing may help to improve outcomes in this setting. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 21) who received haplo-HCT from 2014 to 2019. The primary end-point assessed was 1-year GVHD-free/relapse-free survival (GRFS) defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. Secondary end-points included 1-, 2-, and 3-year relapse-related mortality (RRM) and overall survival (OS) in addition to 1-year transplant related mortality (TRM) and incidence of both acute and chronic GVHD. Results: A total of 67 adult haplo-HCT recipients were reviewed. Of the patients evaluated, approximately 50% (n = 33) were male and 49% (n = 32) were female. The age range was 21-71 years old (median = 44), and the most common underlying hematologic disorders included AML (40%), ALL (38%), aplastic anemia (7.7%), and others (MDS, lymphoma, myelofibrosis, and HLH) (13.8%). 67% of patients received myeloablative conditioning regimens while 33% received reduced intensity regimens. 70% (n = 47) of patients received peripheral blood as a stem cell source with 30% (n = 20) receiving bone marrow. The mean CD34+ dose infused was 6.07x106 cells/kg and the mean CD3+ dose was 2.94x108 cells/kg. The mean time to recovery of platelets, neutrophils, and lymphocytes was 25, 18, and 37 days respectively. CD34+ stem cells ≥5.00x106 cells/kg was significantly associated with shorter time to lymphocyte recovery (p = 0.0265) though recovery less than 30 days was not significantly associated with OS (p = 0.5268). Incidence of 1-year GRFS was 71% (n= 46) and 1-, 2-, and 3-year RRM were 4.6%, 6%, and 7.7% respectively. 1-year TRM was 15.3% with 50% of deaths from acute GVHD. 1-, 2-, and 3-year OS were 80%, 78%, and 77% respectively. Factors significantly associated with increased mortality included use of RIC regimen (p = 0.004) and disease status at time of transplant (p = 0.04). Cumulative incidence of GVHD was 63% (n = 42) with 33% (n = 22) and 30% of patients (n = 20) with acute and chronic GVHD respectively. Lack of mild chronic GVHD was associated with increased mortality (p = 0.0029) and use of a myeloablative regimen (p = 0.0029) was significantly associated with GVHD. Subgroup analysis of those who received CD34+ dose ≥7.00x106 cells/kg (n = 24) and ≥10x106 cells/kg (n = 7) were found to have 1-year OS of 87.5% and 85.7% compared with 77% and 80% in those that received lower doses (p= 0.2229 and p = 1.00) respectively however this was not found to be significantly associated with increased incidence of GVHD, relapse, or mortality. Discussion: Our results demonstrate improved outcomes specifically 71% survived 1 year without experiencing at least 1 GRFS event compared with 24-35% reported by CIBMTR, Holtan et al 2015, and Solh et al 2016 with 3-year OS of 77% when compared with a previously reported 48%. The mean CD34+ cell dose of our population is higher than the standard range which may account for the improved outcomes however the dosing of CD34+/CD3+ cells were not significantly associated with our primary and secondary end-points. It was significantly associated, however, with shorter time to lymphocyte recovery, a factor that has been reported to be associated with decreased RRM and therefore improved OS. Furthermore, subgroup analysis of higher CD34+ dose did show a better 1-year OS though this was not statistically significant. Limitations of this study include small sample size and short follow-up period. Further research with a prospective study identifying the optimal CD34+/CD3+ cell dose in addition to comprehensive evaluation of immune recovery is warranted in order to improve haplo-HCT outcomes. Figure Disclosures Yaghmour: Jazz Pharmaceutical company: Consultancy, Speakers Bureau; Astella company: Speakers Bureau; Takeda: Speakers Bureau.

Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 730-730 ◽  
Author(s):  
Edwin P. Alyea ◽  
Shuli Li ◽  
Haesook Kim ◽  
Corey Cutler ◽  
Vincent Ho ◽  
...  
Keyword(s):  
Serum Level ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Dose Methotrexate ◽  
Gvhd Prophylaxis ◽  
Low Incidence

Abstract Sirolimus (rapamycin) is a macrocyclic lactone similar in structure to tacrolimus and cyclosporine (CSA) but with a distinct mechanism of action. Sirolimus binds to both FKBP12 and mTOR and inhibits signal transduction and cell cycle progression. The drug is synergistic with tacrolimus but has a distinct toxicity profile, thereby allowing their use in combination. We report results of a phase II trial combining sirolimus with tacrolimus and low-dose methotrexate (MTX) as GVHD prophylaxis in matched related and unrelated donor NST. Results of this trial were compared with patients who had previously undergone NST receiving tacrolimus/MTX alone or CSA/prednisone(pred). All patients received fludarabine (30 mg/m2/d x 4days) and intravenous busulfan (0.8mg/kg/d x 4 days) as conditioning. All patients received G-CSF mobilized peripheral blood stem cells with a targeted cell dose of 1 x 107 CD34+ cells/kg. G-CSF 5 mcg/kg was started on day 1. Sirolimus containing GVHD prophylaxis included sirolimus 12 mg loading dose on day −3 and then 4 mg po qd targeting a serum level of 3–12 ng/ml. Tacrolimus was initiated at 0.05 mg/kg po b. i.d. beginning day −3 with a targeted serum level of 5–10 ng/ml. MTX (5 mg/m2) was given days, 1, 3 and 6. Planned taper of the GVHD medications was ~30% at days 60, and 120 with discontinuation by day 180. The median follow up is 14 months for patients receiving sirolimus and all evaluable patients have been followed for >100 days. 40 patients have been transplanted, 20 from related and 20 from unrelated donors. The median age was 57 years (range 20–69). Diseases included: NHL (9), MDS (7), Hodgkin’s disease (6), CLL (6), AML(5), CML (5), MM (1) and CMML(1). 18 patients (45%) had received prior myeloablative transplantation. 31 patients (78 %) had advanced disease at the time of transplantation. Patients receiving tacrolimus/MTX (n=36) and CSA/pred (n=49)had similar characteristics. Sirolimus was well tolerated and no severe adverse events related to the drug were noted. Acute grade 2–4 GVHD was significantly reduced in patients receiving sirolimus/tacrolimus/MTX, 8% vs 18% in patients receiving tacrolimus/MTX and 37% in those receiving CSA/Pred (p=0.003). Time to neutrophil engraftment was slower in methotrexate containing regimens (13 days vs 9 days, p=0.01), but there was no difference between sirolimus/tacrolimus/MTX and tacrolimus/MTX alone. Median donor derived hematopoiesis, measured 1–2 months after transplant, was high in all groups (sirolimus/tacrolimus/MTX 91%, tacrolimus/MTX 95% and CSA/pred 90%, p=0.91). The 1 year overall survival was sirolimus/tacrolimus/MTX 71%, tacrolimus/MTX 48% and CSA/pred 45% (p=0.17). 1-year progression free survival was 49%, 27% and 37%, respectively (p=0.11). The addition of sirolimus to tacrolimus and low dose MTX is well tolerated and is associated with a low incidence of acute GVHD. The addition of sirolimus does not delay engraftment compared with tacrolimus/MTX and results in a similar high level of donor derived hematopoiesis. Further patient accrual and longer follow-up is needed to yield information on the incidence of chronic GVHD and overall outcome.

Outcome of Patients Developing GVHD after DLI for CML Relapse from HLA-Identical Sibling or VUD HSCT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1817-1817
Author(s):  
Yves Chalandon ◽  
Christoph Schmid ◽  
Kimmo Porkka ◽  
Alvaro Urbano-Ispizua ◽  
Bernd Hertenstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Median Number ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Initial Cell ◽  
Cell Dose ◽  
Stem Cell Source ◽  
Related Mortality

Abstract Using data submitted to the EBMT registry, we analyzed outcome on 344 patients (pts) who had received donor lymphocyte infusions (DLI) for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) in 31 centers. 113/344 pts (33%) developed acute graft-versus-host disease (aGVHD) a median of 50 days post DLI (max grade: I=42, II=30, III=31, IV=6)(60% grade II–IV). Organs involved (%): skin (88), liver (42), gut (30). Median age was 38 (4–59), 58% pts were male, 62 transplants were HLA-identical sibling and 51 unrelated. 74 were T-cell depleted, 92 transplanted in CP1, 21 beyond CP1. Relapse was molecular in 19 pts, cytogenetic in 31, hematological in 49, accelerated or blastic in 12. Median initial cell dose was 107CD3+ cells/kg (0.01–32), median number of DLI was 1 (1–10). aGvHD was treated with prednisone in 92% of pts, CSA in 52 %, ATG and monoclonal antibodies in 2% and other in 19%. aGVHD resolved in 53% of the pts within a median of 63 d (7–546). 82/344 pts (24%) had chronic GVHD (cGVHD)(30 limited, 50 extensive, 2 not specified), of those 46 (56%) following aGVHD post DLI. Organs involved (%): skin (75), liver (35), lungs (13), mouth (43), eyes (22) and gut (5). Median age was 35 (6–58), 51% were male, stem cell source was PB in 15% and marrow in 85%, 43 underwent HLA-identical sibling HSCT and 39 unrelated donor HSCT. Forty-three were T-cell depleted, 66 transplanted in CP1, 16 beyond CP1. Relapse was molecular in 21 pts, cytogenetic in 29, hematological in 22, accelerated or blastic in 7. Median initial cell dose was 107 CD3+ cells/kg (0.05–40), median number of DLI was 1 (1–7). 61 pts are alive with a median follow-up of 50 mth. Treatment was with steroids in 83% of pts, CSA in 58 %, MMF in 20%, thalidomide in 15%, photopheresis in 15%, PUVA in 10% and other in 17%. cGVHD resolved in 39% of the pts within a median of 354 d (44–1588). The estimated 5-y OS post-DLI was significantly lower in pts who developed aGVHD post-DLI, 61 ± 10% vs 74 ± 7% in the one that did not, p=0.007 and also a tendency to have a lower 5-y EFS, 58 ± 10% vs 65 ± 7%, p=0.19. Median duration of response to DLI in aGVHD pts was 4 y. aGVHD post-DLI did not influence the relapse rate (5 ± 5% vs 6 ± 5% in the absence of aGVHD). 5-y DLI related mortality was significantly higher in aGVHD pts, 31 ± 8% vs 4 ± 4%, p<0.00001. On the other hand, pts that developed cGVHD post-DLI had a tendency to have a better 5-y OS and EFS, 74 ± 11% and 71 ± 11% respectively vs 69 ± 6% and 62 ± 7% in those that did not, p=0.32 and 0.09. This was related to a tendency to lower incidence of relapse, 2 ± 3% in pts with cGVHD vs 9 ± 6% without, p=0.2. DLI related mortality was not different, 11 ± 8% vs 10 ± 5%, p=0.77. aGVHD post-DLI for CML relapse is mainly of advanced stage and negatively influence OS and EFS with a higher DLI related mortality. cGVHD post-DLI is mainly extensive, but pts with cGHVD tend to have better outcome with better 5-y OS, EFS and less relapse than those without, although this was not statistically significant.

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