Disease-Free Survival in Adult Patients with Acute Leukemia and Advanced CML Supports Use of Double-Unit Cord Blood Grafts As an Immediate Alternative to 8/8 HLA-Matched Unrelated Donors (URD)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2588-2588
Author(s):  
Doris M. Ponce ◽  
Patrick Hilden ◽  
Sean M. Devlin ◽  
Molly Maloy ◽  
Marissa N Lubin ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Acute Leukemia ◽  
Cord Blood ◽  
Acute Gvhd ◽  
Disease Free Survival ◽  
Adult Patients ◽  
High Dose ◽  
Free Survival ◽  
Disease Free

Abstract Background: Double-unit cord blood transplantation (DCB-T) is a rapidly available alternative to unrelated donor transplantation (URD-T) for patients with high-risk acute leukemia or advanced CML. Retrospective analyses in adult DCB-T suggest that double-unit CB grafts may be associated with improved disease-free survival (DFS). However, the prioritization of URD-T vs DCB-T is controversial. Methods: We evaluated 175 consecutive adult allograft recipients (120 URD-T and 55 DCB-T) aged 16-60 years transplanted 10/2005-11/2012 for acute leukemia in morphologic remission or aplasia (113 AML/ biphenotypic, 50 ALL), or advanced CML (n = 12). URD grafts were 7-8/8 HLA-matched (74 8/8, 46 7/8). CB grafts were 4-6/6 donor-recipient HLA-matched (4 6/6, 51 5/6, 55 4/6). All patients received either high dose or reduced intensity myeloablative conditioning. The majority of URD-T recipients (n = 111, 93%) received T-cell depleted (TCD) grafts with rabbit ATG, whereas GVHD prophylaxis for DCB-T was calcineurin-inhibitor/mycophenolate mofetil. Results: The median ages of URD-T (43 years) and DCB-T (42 years) recipients were similar (p = 0.713). Distributions of gender, recipient CMV positivity, HCT-CI scores, time from diagnosis or relapse to transplant, diagnoses, disease risk, and percentage of patients with minimal residual disease pre-transplant were also similar. Neutrophil engraftment was slower in DCB-T (95%, median 24 days) than URD-T (100%, median 11 days) (p <0.001). While the incidence of grade II-IV acute GVHD at day 100 was lower in TCD URD-T recipients (15%) than in unmodified URD-T (56%) and DCB-T (55%), p = 0.002, the incidence of day 100 grade III-IV acute GVHD was similar in TCD URD-T, unmodified URD-T, and DCB-T recipients (p = 0.794). With a comparable survivor follow-up [URD-T median 51 months (range 15-99) vs DCB-T median 46 months (range 15-92)], transplant-related mortality was similar (3-year estimates: URD-T 25% vs DCB-T 24%, p = 0.838) whereas the relapse risk was decreased after DCB-T (3-year estimates: URD-T 23% vs DCB-T 9%, p = 0.008). Overall, the 3-year DFS after URD-T was 52% and 68% after DCB-T (p = 0.056). When split into 3 groups, the 3-year DFS was 59% in 8/8 URD-T, 40% in 7/8 URD-T, and 68% in DCB-T, p = 0.043 (Figure). Multivariate analysis was performed to determine risk factors for disease relapse or death in the 175 patients (Table). Female gender (HR 1.65, p = 0.029), diagnosis of ALL (HR 2.11, p = 0.002), and mismatched URD-T (HR 1.97, p = 0.027) were each significantly associated with treatment failure. Conclusions: DCB-T can achieve favorable DFS in adults with acute leukemia and CML with low relapse rates. In this series, multivariate analysis demonstrated that mismatched URD-T was independently associated with lower DFS. Our findings support use of DCB-T as an immediate alternative for high-risk acute leukemia and advanced CML in adult patients without a readily available 8/8 allele HLA-matched unrelated volunteer donor. This could have the additional benefit of speeding time to transplant in high-risk patients. Table Variable MultivariateHR (95% CI) P-value Male Female Reference 1.65 (1.05-2.59) 0.029 Recipient CMV Negative Recipient CMV Positive Reference 1.34 (0.85-2.12) 0.201 HCT-CI score 0-2 HCT-CI score > 3 Reference 1.56 (0.98-2.47) 0.059 AML/CML ALL Reference 2.11 (1.30-3.41) 0.002 DCB-T 8/8 URD-T 7/8 URD-T Reference 1.32 (0.72-2.41) 1.97 (1.08-3.60) - 0.365 0.027 Figure Figure. Disclosures No relevant conflicts of interest to declare.

Double-Unit Cord Blood Transplantation (DCBT) for Acute Leukemia: High Disease-Free Survival in Adults and Children with Comparable Survival in European and Minority Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3080-3080
Author(s):  
Juliet N Barker ◽  
Doris M Ponce ◽  
Anne Marie R Gonzales ◽  
Marissa N Lubin ◽  
Hugo Castro-Malaspina ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
European Ancestry ◽  
High Dose ◽  
Free Survival ◽  
Disease Free

Abstract Abstract 3080 As compared to single-unit CBT, DCBT may improve engraftment and protect against relapse. Therefore, we have adopted DCBT for both children and adults with acute leukemia, myelodysplasia (MDS), and myeloproliferative diseases (MPD). However, determinants of disease-free survival (DFS) have yet to be fully established. Furthermore, whether DFS after DCBT is comparable in patients of European and non-European ancestry is of special interest. Therefore, we analyzed the DFS of 75 DCBT recipients with acute leukemia in morphologic remission or aplasia (n = 69), and MDS/MPD with ≤ 5% blasts (n = 6) transplanted from 10/2005-4/2011. Nearly all patients had high-risk disease. Children 0–15 years (n = 23) had the following characteristics: median age 9 years (range 0.9–15); median weight 37 kg (range 7–72); 30% European; and 26% CMV sero-positive. Diagnoses were 43% AML (or biphenotypic), 52% ALL, and 4% MDS/MPD, and all received high-dose conditioning. The children received grafts with a median infused TNC × 107/kg of 3.3 (larger unit) and 2.6 (smaller unit), and 2% of units were 6/6 HLA-A, -B antigen, -DRB1 allele matched, 63% 5/6, and 35% 4/6. Adults ≥ 16 years (n = 52) had the following characteristics: median age 41 years (range 16–69); median weight 69 kg (range 47–105); 48% European; 69% CMV sero-positive; and diagnoses were 63% AML (or biphenotypic), 27% ALL, and 10% MDS/MPD. Fifty percent received high-dose and 50% reduced intensity conditioning. Their units had a median infused TNC/kg of 2.7 and 1.9, and 3% were 6/6 HLA-matched, 47% 5/6, and 50% 4/6. All patients (pediatric and adult) received calcineurin-inhibitor/ mycophenolate mofetil immunosuppression, and none received anti-thymocyte globulin. Sustained donor neutrophil engraftment was seen in 91% of children and 94% of adults at medians of 20 and 26 days, respectively. The incidence of grade II-IV acute GVHD by day 180 was 44% in children and 58% in adults. Day 100 transplant-related mortality (TRM) was 9% in children and 19% in adults. The 2-year relapse incidence was 9% in children and 6% in adults. With a median follow-up of survivors of 26 months (range 4–70), 2-year Kaplan-Meier estimate of DFS was 78% in children and 64% in adults (Figure). Differences in survival by age did not reach significance. Univariate analysis of variables potentially influencing 2-year DFS (with log rank estimates of significance) in all patients is shown in the Table. There were no differences in 2-year DFS according to ancestry, remission status, and conditioning intensity. There was also no difference in 2-year DFS according to engrafting unit-recipient HLA-match (4-6/6 or 10 allele), or engrafting unit infused TNC dose/kg. However, patients who were CMV seronegative had a higher 2-year DFS (85% vs 55%, p = 0.018). Multivariate analysis revealed recipient CMV serostatus was a predictor of DFS independent of patient age, and its effect was mediated by an influence on TRM. We have previously shown that DCBT extends transplant access to minority patients. We now demonstrate that DCBT can achieve high and comparable DFS in both European and non-European pediatric and adult patients with acute leukemia and MDS/MPD. While these are very encouraging results further investigation in racial/ethnic sub-groups is needed. Nonetheless, our findings support DCBT as an immediate alternative therapy for high-risk acute leukemia in patients without suitable unrelated volunteer donors, especially given the very low incidence of relapse. Disclosures: No relevant conflicts of interest to declare.

Myeloablative Double-Unit Cord Blood Transplantation (CBT) in Pediatric Patients with High-Risk Acute Leukemia Demonstrates Encouraging Disease-Free Survival with Both TBI and Chemotherapy-Only-Based Conditioning

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2578-2578
Author(s):  
Andromachi Scaradavou ◽  
Marissa N Lubin ◽  
Patrick Hilden ◽  
Farid Boulad ◽  
Kevin J. Curran ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Cumulative Incidence ◽  
Single Unit ◽  
Acute Gvhd ◽  
Disease Free Survival ◽  
European Ancestry ◽  
Platelet Recovery ◽  
Free Survival ◽  
Disease Free

Abstract Introduction: Double-unit CBT (DCBT) in adult patients (pts) with hematologic malignancies has been associated with high rates of disease-free survival (DFS) but its role in children is controversial. Methods: We investigated DCBT in children with high-risk acute leukemia following TBI or chemotherapy-based myeloablative cytoreduction. Outcomes of consecutive DCBT pts transplanted 10/2005-2/2013 as their first allograft were evaluated. Results: Thirty-five pts [median age 7.5 yrs (range 0.8-18), median weight 28 kg (range 8-75)] were transplanted. Seventeen had acute myelogenous or biphenotypic leukemia (AML): 6 in CR1 (one each with M7, secondary 5q- MDS, FLT-3 ITD mutation, Ph+, Down syndrome with positive MRD, or germline mutation CEBPa), 8 in CR2 (one with MLL positive MRD), 2 in aplasia, and one in CR3. Seventeen pts had ALL: 10 in CR1 [3 Ph+ (one with MRD), 2 T-cell ALL, one MLL, one L3 disease, and 3 multiple inductions], 4 in CR2, and 3 in CR3. One pt had CML (imantinib resistant, accelerated phase with MRD). Thirty-one percent were CMV seropositive and 69% had non-European ancestry. Conditioning was cyclophosphamide/fludarabine/TBI 1375 cGy (N=21, 60%), or in the very young or those with prior radiation a chemotherapy-based regimen was used (N=14, 40%, 10 with clofarabine/thiotepa/melphalan and 4 with busulfan/melphalan/thiotepa). GVHD prophylaxis was with calcineurin-inhibitor/mycophenolate mofetil. Units had a donor-recipient 4-6/6 HLA-A,-B antigen,-DRB1 allele match, a cryopreserved total nucleated cell (TNC) dose >1.5 x 107/kg/unit, and were albumin reconstituted for pts >20 kg or washed for smaller pts. The cumulative incidence of sustained donor neutrophil engraftment was 94% (95%CI:78-98, median 21 days, range 12-33) and hematopoiesis was mediated by a single unit. Day 180 platelet engraftment >50 x 109/l was 82% (95%CI: 64-92). The median platelet recovery in 31 evaluable pts was 51 days (range 39-299). Immune recovery was prompt with a mean absolute CD4+ count of 201 (SD:+/-180) at day +60, and 250 (SD:+/-150) at day +120. The engrafting unit had a median infused TNC dose of 3.9 x 107/kg (range 0.9-12.8) and 10/33 (30%) pts engrafted with a unit that had a pre-cryopreservation TNC <2.5x107/kg. In addition, the majority (17/33, 51%) of pts engrafted with a unit that was <5/8 HLA-allele matched to the recipient (range 2-5/8). The cumulative incidence of day 100 grade II-IV acute GVHD was 46% (95%CI:29-61) and 23% (95%CI:11-38) of pts had grade III-IV acute GVHD. The 3-year incidence of chronic GVHD was 14% (95%CI:5-28). With a median survivor follow-up of 58 months (range 20-105), the 3-year cumulative incidences of transplant-related mortality (TRM) and relapse were 11% (95%CI:4-24) and 20% (95%CI:9-35), respectively. Transplant-related causes of death were 2 graft failures, 1 HHV-6 encephalitis (day +53) and 1 RSV/metapneumovirus pneumonia (day +28). While some pts with GVHD required prolonged immunosuppressive therapy, none died of GVHD. Of the 7 children with relapse, 2 had AML in CR1 (one FLT-3 ITD mutation, one M7 AML), one had primary refractory AML transplanted in aplasia, and 4 had ALL (2 CR1, 1 CR2, 1 CR3). None of the 4 pts transplanted with MRD relapsed. Three-year DFS was 68% (95%CI:50-81). There was no difference based on diagnosis (3-yr DFS 77% in AML and 59% in ALL, p = 0.25, Figure), TBI-based cytoreduction (p = 0.68), or European vs non-European ancestry (p = 0.24). Positive recipient CMV serostatus was associated with lower DFS in univariate analysis (p = 0.005) with 5/11 CMV+ pts relapsing. Conclusions: Despite high-risk disease and grafts with a very high degree of donor-recipient HLA-allele mismatch, the low TRM and relapse rates after pediatric DCBT are striking. Although many of the younger children could have had “adequate” single unit grafts based on the recently published CIBMTR definition (cryopreserved TNC >3.0 x 107/kg and 6-8/8 allele HLA-match), a significant minority will not. Therefore, despite the lack of benefit of DCBT in the BMT CTN randomized study, DCBT remains an important consideration in children, especially in those of non-European ancestry. Finally, chemotherapy-only-based conditioning is an effective alternative to high-dose radiation, an approach that further extends transplant access to pts unsuitable for TBI. Figure: 3-yr DFS after DCBT in children with high-risk acute leukemia Figure:. 3-yr DFS after DCBT in children with high-risk acute leukemia Disclosures Boulad: Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other.

scholarly journals Predictive Ability for Disease-Free Survival of the GRade, Age, Nodes, and Tumor (GRANT) Score in Patients with Resected Renal Cell Carcinoma

2020 ◽  
Vol 14 (2) ◽  
pp. 98-104
Author(s):  
Alessio Cortellini ◽  
Sebastiano Buti ◽  
Melissa Bersanelli ◽  
Katia Cannita ◽  
Giada Pinterpe ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Multivariate Analysis ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Disease Free Survival ◽  
Free Survival ◽  
Risk Of Recurrence ◽  
Significant Difference ◽  
Disease Free

Background: Recently, the GRANT (GRade, Age, Nodes, and Tumor) score was validated through an adjuvant trial population. Methods: This retrospective study evaluated the performance of the GRANT score as a prognostic model for disease-free survival (DFS), compared to the University of California Los Angeles Integrated Staging System (UISS) score, in a “real-life” population of early renal cell carcinoma patients. A uni-/multivariate analysis of DFS was also performed, to weigh the roles of baseline clinical factors. Results: From February 1998 to January 2018, 134 consecutive patients were enrolled, of which 85 patients (63.4%) had a favorable GRANT score, 49 (36.6%) an unfavorable GRANT score, and 21 (15.7%), 84 (62.6%), and 29 (21.6%) patients had a low, intermediate, or high risk of recurrence according to the UISS score, respectively. The median follow-up was 96 months. The median DFS of the overall study population was 53.7 months (95% CI: 38.4-87.8). Only bilateral renal cell carcinoma (p = 0.0041), Fuhrman grade 3/4 (p = 0.0008), pT3b- 4 (p = 0.0324), and pN1-2 (p = 0.0303) pathological status were confirmed as independent predictors of a shorter DFS by the multivariate analysis. The median DFS of patients with favorable and unfavorable GRANT scores were 84.9 (95% CI: 49.8-129) and 38.4 months (95% CI: 24.4-87.8), respectively, with a statistically significant difference (p = 0.0147). The median DFS of patients with low, intermediate, and high risk of recurrence according to the UISS score were 92.3 (95% CI: 18.1-153.9), 51.7 (95% CI: 36.2-87.8), and 49.8 months (95% CI: 31.3-129), respectively, without statistically significant differences (p = 0.4728). DFS c-statistic values were 0.59 (95% CI: 0.51-0.67) and 0.51 (95% CI: 0.42-0.60) for the GRANT and the UISS scores, respectively. Conclusion: The GRANT score might be a useful tool that is user-friendly and easy to perform in clinical practice.

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

Augmented Hyper-CVAD in Adult ALL Salvage Therapy: The MDACC Experience of Hyper-CVAD Using Dose-Intense Vincristine, Dexamethasone, and Pegaspargase.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2031-2031 ◽  
Author(s):  
Mohamad Ayoubi ◽  
Deborah A. Thomas ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Median Number ◽  
Adult Patients ◽  
High Dose ◽  
Cell Transplant ◽  
Refractory Disease ◽  
Free Survival ◽  
Comparable Activity ◽  
Long Acting ◽  
Disease Free

Abstract Abstract 2031 Poster Board II-8 Adult patients (pts) with ALL have inferior outcome compared children with a higher relapse rate and shorter disease-free survival. The prognosis remains especially poor for adults with relapsed or refractory disease. Recent studies in adolescents and young adults demonstrated better outcome when postremission therapies were intensified. Following this lead and based on our experience with hyper-CVAD (up to 8 cycles of fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine followed by maintenance therapy) we designed an augmented version of hyper-CVAD including intensified doses of vincristine, dexamethasone, and asparaginase. We have previously reported experience in 55 pts treated with augmented hyper-CVAD using L-asparaginase (Faderl et al. Blood 2007; 110: 149b). In the current extension of the trial we replaced L-asparaginase with pegaspargase, a long-acting formulation of asparaginase, which has been reported to be at least as effective and less immunogenic than L-asparaginase. With each course of hyper-CVAD and methotrexate/cytarabine, pts received vincristine 2 mg iv x 3, dexamethasone 80 mg iv/po on days 1-4 and 15-18, and pegaspargase 2,500 units/m2 iv x 1. From September 2008 until July 1009, 24 pts with relapsed/refractory ALL have been enrolled. Median age was 31 yrs (range 20-61). Nineteen pts (79%) had pre-B ALL, 4 (17%) pre-T ALL, and one pt had biphenotypic leukemia. Median number of prior regimens was 1 (range 1-4). Two pts relapsed from prior stem cell transplant (SCT). Two pts had primary refractory disease. Median remission duration to the initial induction regimen of the remainder of the pts was 37 months (range 2-78). Cytogenetics were diploid in 9 pts (38%), abnormal in 7 (29%), and not available in 8. Twenty pts are evaluable for response. Nine (45%) pts achieved CR and 7 (35%) CRp for an OR rate of 80%. Median time to CR was 34 days (range 20-80). Among the 9 CR pts, median CR duration is 3.4 months (0.4+-6.7+), CR is ongoing in 5 patients, and 6 were referred to SCT. Three pts (15%) died while on study from sepsis and myelosuppression-related complications. Neutropenic fever was common. Common non-hematologic adverse events included elevations of bilirubin and transaminases. Pegaspargase was well tolerated and had to be omitted in only 2 pts due to elevation of transaminases. No anaphylactic reactions occurred. Augmented hyper-CVAD has activity in adult patients with relapsed ALL. Pegaspargase appears to have comparable activity and less toxicity than L-asparaginase. Further studies in an adult frontline population should be considered. Disclosures: Faderl: Enzon: Research Funding.

Germline Genetic Polymorphisms Are Associated with Disease-Free Survival in Adults with Acute Myeloid Leukemia (AML): A Genomewide Association Study From the Pgrn-Riken Global Alliance.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2548-2548
Author(s):  
Sook Wah Yee ◽  
Joel Mefford ◽  
John Witte ◽  
Michiaki Kubo ◽  
Koichi Matsuda ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Disease Free Survival ◽  
Adult Patients ◽  
Population Substructure ◽  
Baseline Risk ◽  
Patient Specific ◽  
P Value ◽  
Free Survival ◽  
Disease Free

Abstract Abstract 2548 Background: AML is a malignancy with an average five-year survival rate of 50% in adults. Great strides have been made in deciphering the genetic heterogeneity of this disease and indentifying subgroups with favorable or unfavorable outcomes based on cytogenetic and molecular factors. We undertook this study to identify patient-specific germline determinants of treatment outcome and survival in AML. Methods: Our cohort was comprised of 314 adult patients with AML in first or subsequent complete remission who underwent consolidation therapy with a busulfan-based autologous stem cell transplant (Bu-ASCT) at UCSF between 1986 and 2009. DNA samples were isolated from patients' peripheral blood mononuclear cell alliquots collected via apheresis following etoposide and high-dose cytarabine consolidation at the time of confirmed complete remission. Genotyping was performed using the Illumina Human OmniExpress Beadchip. To adjust for population substructure, EIGENSTRAT software was used to determine eigenvalues for the SNP correlation matrix and the corresponding eigenvectors were used as covariates. Statistical analyses were conducted with STATA and PLINK software. Association testing with DFS was based on Cox proportional hazards models. We utilized a multiplicative (log-additive) model with a genome wide-alpha set at 10−8. The subset of 168 genetically European patients (cau) was used for the primary analysis. Results: Overall, 9.7% of patients in our cohort had high-risk/relapsed acute promyelocytic leukemia, 12.9% core-binding factor leukemia [inv 16 or t(8;21)], 69.5% cytogenetically-normal leukemia, and 7.9% high-risk disease either by cytogenetic or molecular abnormalities. Disease-free survival in our cohort following Bu-ASCT was 59% at 5 years. As expected, baseline risk was significantly associated with DFS but treatment era was not. We identified several significant SNP clusters in our analysis. A 4-SNP cluster emerged on chr15 with a SNP ranked 2nd and one ranked 8th in the overall analysis. The SNP (rs933813) marked 2nd was upstream of the insulin-like growth factor-1 receptor (IGF1R). After adjustment for baseline risk, this SNP was significantly associated with DFS in cau (p-value= 6.9×10−8) as well as the overall population (p-value= 1.1×10−6). Other clusters are being evaluated. Conclusions: We identified several significant SNPs and SNP clusters that are associated with DFS in adult patients with AML undergoing Bu-ASCT. So far a SNP upstream of IGF1R has emerged as highly significant in our analysis. Ongoing studies are focusing on imputation, fine mapping and functional validation of these results. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1259-1259
Author(s):  
Doris M. Ponce ◽  
Rodney Sparapani ◽  
Junfang Chen ◽  
Vanderson Rocha ◽  
Daniel H. Fowler ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Disease Status ◽  
Free Survival ◽  
Grade Ii ◽  
Disease Free ◽  
Grade Iii

Abstract Background: Cord blood (CB) is routinely used as an alternative stem cell source for the treatment of children with acute leukemia and has been associated with high rates of disease-free survival (DFS). However, one controversial issue in pediatric CB transplantation is the role of anti-thymocyte globulin (ATG) as immunoprophylaxis. While inclusion of ATG in the conditioning may decrease the risk of graft-versus-host disease (GVHD), it could potentially abrogate graft-versus-leukemia effects and increase the risk of opportunistic infections. Thus, we compared outcomes in a uniform group of pediatric patients with acute lymphoblastic leukemia (ALL) who underwent myeloablative CB transplantation with or without ATG. Methods: Patients with ALL in morphologic remission (CR1 n=106, CR2 n=146, CR3 n=45) aged ≤ 20 years transplanted between 01/2007-12/2011 with high-dose total body irradiation-based conditioning and single or double unit CB grafts were eligible for analysis. CB units were 4-6/6 HLA-A,-B at the antigen-level, -DRB1 allele matched to the recipient and had CB unit with cryopreserved total nucleated cell dose of ≥ 2.5 x107/kg/unit. Cox regression models were built to evaluate potential differences in outcome in ATG versus non-ATG CB transplant recipients. The primary endpoint was 3-year DFS. Results: Of 297 patients, 92 received ATG and 205 did not. Age and disease status were similar in each group whereas ATG recipients were less likely to be CMV seropositive and more likely to receive single unit CB grafts. While neutrophil engraftment was similar in each group, the risk of day 100 grade II-IV acute GVHD [30% (95%CI: 21-40) versus 54% (95%CI: 47-61), p = 0.0002] and 3-year chronic GVHD [22% (95% CI: 14-31) versus 43% (95% CI: 36-50), p = 0.0008] were decreased in ATG recipients. However, day 100 grade III-IV aGVHD was comparable: 11% (95%CI: 5-18) in ATG versus 17% (95%CI: 12-23) in non-ATG recipients, p = 0.15]. The 3-year TRM was similar in both groups: 16% (95%CI: 10-25) in ATG versus 17% (95%CI: 13-23) in non-ATG recipients (p = 0.98). Relapse was also similar in ATG and non-ATG recipients: 17% (95%CI: 10-23) versus 27% (95%CI: 21-34, p = 0.12), respectively. In multivariate analysis, negative CMV serostatus was associated with reduced TRM risk [HR 0.55 (95%CI: 0.30-0.98), p = 0.004] whereas remission status CR2 or CR3 significantly increased relapse risk [HR 2.18 (95%CI: 1.22-3.89), p = 0.008], but inclusion of ATG had no effect on either outcome. With a median follow-up of survivors of 36 months (range 5-72), the 3-year DFS was 66% (95%CI: 56-76) and 55% (95%CI: 48-62) in ATG and non-ATG recipients, respectively (p = 0.23, Figure 1). The distribution of causes of death was similar in each group. In multivariate analysis, treatment failure risk was increased in patients transplanted in CR2 or CR3, but the inclusion of ATG had no effect (p = 0.24) (Table 1). Conclusion: Inclusion of ATG in pediatric myeloablative CB transplant for ALL is associated with a decreased risk of grade II-IV acute GVHD and chronic GVHD but not severe grade III-IV acute GVHD. There was no difference in 3-year DFS in each group and multivariate analysis revealed ATG inclusion had no impact upon treatment failure risk. These results indicate that optimization of both ATG and non-ATG conditioning platforms are needed in order to further improve CB transplantation survival in children with ALL. Unanswered questions include the impact of the formulation, dose and timing of ATG administration. These findings cannot be extrapolated for other diagnoses, reduced intensity conditioning, or adults. Table 1 Hazard ratio(95% confidence interval) p-value ATG use Conditioning without ATG Conditioning with ATG 1.00 0.78 (0.52 – 1.18) 0.24 Disease status CR1 CR2, CR3 1.00 2.01 (1.31 – 3.08) 0.001 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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