Impact of GvHD and Other Patient-, Disease-, Donor and Transplantation-Related Factors on 5 Year Relapse after Unrelated Cord Blood Transplantation for Children with Acute Lymphoblastic Leukemia in Remission

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4384-4384
Author(s):  
Kristin M Page ◽  
Myriam Labopin ◽  
Annalisa Ruggeri ◽  
Gerard Michel ◽  
Cristina Diaz de Heredia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cord Blood ◽  
B Cell ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Poor Risk ◽  
Younger Age ◽  
Unrelated Cord Blood ◽  
The Impact

Abstract Relapse remains a major barrier to the long-term overall survival (OS) of pediatric patients with acute lymphoblastic leukemia (ALL). Allogeneic HSCT is a potentially curative option for these patients and its mechanism relies on graft-versus-leukemia (GvL) and delivery of high-dose chemotherapy. However, the mechanism and degree of GvL in curing ALL is not fully understood. Unrelated cord blood (CB) is an attractive donor option for these patients due to rapid procurement and lenient HLA matching without increased graft-versus-host disease (GvHD). Despite less GvHD, relapse is not increased when compared to other donor sources. Therefore, through collaboration between Eurocord, PDWP-EBMT and Duke University, we performed a retrospective analysis to identify risk factors associated with relapse, and the role of GvHD (as time dependent co-variate) in preventing relapse after unrelated CB transplantation (CBT) for children with ALL. We analyzed 640 children (<18 years (y)) with ALL in complete remission (CR) who received a single-unit CBT in either first (n=257, 40%) or second (n=383, 60%) CR from 2000-2012. Most patients were diagnosed with B-cell (79%) or T-cell (18%) lineage ALL and had no CNS involvement (92%). Cytogenetic data was available for 411 patients (CR1=171, CR2=240), and 37% were considered intermediate risk and 36% poor risk. Pre-transplant, 49% of patients were CMV seropositive. All patients received myeloablative regimens and most received anti-thymocyte globulin (88%). Regimens included total body irradiation (TBI; 69%) with either cyclophosphamide (Cy)+Fludarabine (Flu; 10%) or other agents (59%), Busulfan (Bu)+ Cy (16%), or Thiotepa+Bu+Flu (8%). Most patients received HLA mismatched CBs at 1 (50%) or 2+ (34%) loci. GvHD prophylaxis included cyclosporine with either steroids (72%) or mycophenolate mofetil (21%), or other agents (6%). Considering CR1 patients only, the median age at CBT was 5.3 y. Most were diagnosed with B-cell ALL (75%) and approximately half of those with known cytogenetics were considered poor risk. The median duration from diagnosis to CBT was 6.7 months and median follow up was 47 months. Estimated OS and LFS at 5 y for CR1 patients was 59% and 52%, respectively. Improved OS and LFS were associated with TBI-containing regimens and younger age at time of CBT (Table 1). The CI of relapse at 5 y was 23% for CR1 patients. In a multivariate analysis (MVA) the presence of acute GvHD (grade II-IV) and TBI-containing regimens were both protective of relapse (Table 1). No impact of GvHD was observed on OS, LFS or NRM. In CR2 patients, the median age at CBT was 6.9 y. Disease was primarily B-lineage ALL (82%) with intermediate or poor risk cytogenetics in 40% and 28% of patients, respectively. Median time from diagnosis to CBT was 36 months and median follow up was 54 months. Estimated OS and LFS in CR2 patients were 46% and 44%, respectively. In MVA, younger age and longer duration from diagnosis to CBT (>30 months) was associated with improved OS and LFS (Table 2). Conversely, the use of ATG was associated with lower OS. In CR2 patients, the CI of relapse was 28%. In MVA, longer duration from diagnosis to CBT (>30 months) and receiving TBI were both associated with less relapse. Importantly, receiving a fully matched HLA CB graft was a strong risk factor for increased relapse compared to mismatched CB recipients. Acute GvHD (II-IV) in this cohort was associated with higher mortality but not with relapse. In this large retrospective collaborative study, we investigated the impact of GvHD as a marker of GvL in pediatric ALL patients after CBT. In CR1 patients, acute GvHD and use of TBI were protective of relapse. However in CR2 patients, use of TBI, longer duration from diagnosis to CBT and HLA mismatched grafts were associated with decreased incidence of relapse but not with the presence of GvHD. These results showed that the impact of GvHD as a GvL marker is more evident in CR1 patients than CR2. Whereas, the impact of HLA mismatch CB on relapse is more important in CR2 patients. Decreasing immunosuppression more rapidly for CR1 patients or avoiding HLA identical CB for CR2 patients should be further investigated. In both cohorts, TBI has shown to be an important protective factor for relapse. Disclosures Bader: Riemser: Other: Institutional grants; Neovii: Other: Institutional grants; Medac: Other: Institutional grants; Amgen: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.

scholarly journals Unrelated cord blood transplant in children with high-risk acute lymphoblastic leukemia: a long-term follow-up

Haematologica ◽  
2007 ◽  
Vol 92 (8) ◽  
pp. 1051-1058 ◽  
Author(s):  
A. P. Iori ◽  
W. Arcese ◽  
F. Milano ◽  
E. Calabrese ◽  
G. F. Torelli ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Cord Blood ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplant ◽  
Long Term Follow Up ◽  
Unrelated Cord Blood

scholarly journals Increase in polymorphonuclear myeloid-derived suppressor cells and regulatory T-cells in children with B-cell acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asmaa M. Zahran ◽  
Azza Shibl ◽  
Amal Rayan ◽  
Mohamed Alaa Eldeen Hassan Mohamed ◽  
Amira M. M. Osman ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Suppressor Cells ◽  
Healthy Controls ◽  
Blast Cells ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Impact

AbstractOur study aimed to evaluate the levels of MDSCs and Tregs in pediatric B-cell acute lymphoblastic leukemia (B-ALL), their relation to patients’ clinical and laboratory features, and the impact of these cells on the induction response. This study included 31 pediatric B-ALL patients and 27 healthy controls. All patients were treated according to the protocols of the modified St. Jude Children’s Research Hospital total therapy study XIIIB for ALL. Levels of MDSCs and Tregs were analyzed using flow cytometry. We observed a reduction in the levels of CD4 + T-cells and an increase in both the polymorphonuclear MDSCs (PMN-MDSCs) and Tregs. The frequencies of PMN-MDSCs and Tregs were directly related to the levels of peripheral and bone marrow blast cells and CD34 + cells. Complete postinduction remission was associated with reduced percentages of PMN-MDSCs and Tregs, with the level of PMN-MDCs in this subpopulation approaching that of healthy controls. PMN-MDSCs and Tregs jointly play a critical role in maintaining an immune-suppressive state suitable for B-ALL tumor progression. Thereby, they could be independent predictors of B-ALL progress, and finely targeting both PMN-MDSCs and Tregs may be a promising approach for the treatment of B-ALL.

Unrelated Cord Blood Transplants in Children/Adolescents in Multi-Racial Singapore.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5089-5089
Author(s):  
Poh-Lin Tan ◽  
Ah-Moy Tan ◽  
Mei-Yoke Chan ◽  
Mariflor Villegas ◽  
Allen Yeoh ◽  
...  
Keyword(s):  
Cord Blood ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Severe Combined Immunodeficiency ◽  
Hla Antigen ◽  
Cell Dose ◽  
Malignant Group ◽  
Unrelated Cord Blood

Abstract Alternative donor choices are limited in multi-racial, multi-ethnic societies with small families such as Singapore. Unrelated cord blood transplant (UCBT) provides a feasible alternative to patients lacking adult stem cell donors. We reviewed the Singapore experience in UCBT for 29 children/adolescents with malignant (N = 19) and non-malignant diseases (N = 10) from 1998 – 2006. A significant 25% of patients were of varied South-East Asian (SEA) descent with majority being SEA-Chinese. The median age at UCBT was 6.7 (0.5 – 17.7) years with younger patients in the non-malignant compared to the malignant group (4.7 versus 8.8 years). Malignant indications for UCBT included acute lymphoblastic leukemia (ALL, N = 12), acute myeloid leukemia (N = 4), chronic myeloid leukemia (N = 2) and hemophagolymphohistiocytosis (N = 1); and non-malignant indications severe combined immunodeficiency disease (N = 3), CD40 ligand deficiency (N = 2), chronic granulomatous disease (N = 1), leukocyte adhesion disease (N = 1), thalassaemia (N = 2) and Fanconi anemia (N = 1). Seventeen patients received myeloablative conditioning (MAC), 12 received reduced intensity conditioning (RIC). Of the 12 RIC patients, 8 received dual UCBT with a median total nucleated cell dose (TNC) of 7.2 (3.4 – 12.2) x 10(7)/kg, CD34 cell dose of 1.7 (0.7 – 3.7) x 10(5)/kg compared to a median 6.2 (2.4 – 21.8) x 10(7)/kg, CD34 of 3.1 (0.2 – 297.6) x 10(5)/kg in MAC patients who received single UCBT.All except 3 patients received 1 – 2 HLA antigen mismatched cords. Sixteen of 19 and 6 of 10 patients in the malignant and non-maligant groups engrafted at a median of 19.5 (2 – 21) days and 20 (14 – 41) days, respectively. Nine and 2 of 17 malignant patients and none of non-malignant patients developed grade 1- III aGVHD and chronic GVHD, respectively. Thirteen of 19 patients and 8 of 10 patients in the malignant and non-malignant groups are alive at a median follow-up of 23 (9 – 48) months and 31 (14 – 73) months, respectively. The main cause of death was disease relapse in the malignant group (5 of 6 patients). In the malignant group, a select group of ALL patients (ALL-RIC, N = 6) was given dual UCBT after RIC with the aim to reduce transplant-related morbidity/mortality while preserving chances of engraftment, graft-versus-leukemia effects and long-term neuro-endocrine outcome. These patients received a median total nucleated cells (TNC) dose of 7.2 (3.4 – 12.2) x 10(7)/kg and CD34 cell dose of 2.0 (0.8 – 3.7) x 10(5)/kg recipient BW and were discharged at a median of 17 (12 – 16) days. Compared to another 6 ALL patients who received single UCBT after MAC (ALL-MAC), these received a median TNC of 5.4 (2.6 – 8.1) x 10(7)/kg and CD34 of 2.8 (0.6 – 297.6) x 10(5)/kg recipient BW and were discharged at a median of 59 (31 – 118) days. ALL-RIC and ALL-MAC patients engrafted at a median of 6 (2 – 28) days and 21 (14 – 37) days, respectively, with one primary graft failure in the ALL-MAC group. There were 4 relapses, 2 in each group at a median follow-up of 23 (12 – 30) months and 16 (3.5 – 48) months, respectively. More patients in ALL-RIC group developed acute GVHD compared to the ALL-MAC (83% versus 33%). All patients except 1 from each group are alive as of last follow-up, with death occurring from a road-traffic accident while in complete remission and one from relapse in the ALL-RIC and ALL-MAC groups, respectively. UCBT successes in children/adolescent is high in multi-racial Singapore using conventional and novel approaches.

Complementary Transplantation with Haploidentical Stem Cells and Unrelated Cord Blood for Leukemia and Thalassemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1235-1235
Author(s):  
Chunfu Li ◽  
Yuelin He ◽  
Xuedong Wu ◽  
Xiaoqin Feng ◽  
Jianyun Liao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cord Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Mixed Chimerism ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Unrelated Cord Blood ◽  
Kinetics Of

Abstract Background Unrelated Cord Blood (UCB) Transplantation is a potentially curative therapy for leukemia and thalassemia; however, engraftment failure and slow immune reconstitution remain key clinical issues. We hypothesized that complementary transplantation (CT) of UCB with haploidentical stem cell graft (hap-SC) tolerized with post-transplant cyclophosphamide would result in rapid engraftment and low relapse rate without additional risk of graft-versus-host disease (GVHD). Therefore, we developed a novel complementary transplant approach. Patients and Method Sixty-six patients received CT between December 2012 and June 2016. Of them, 30 patients had malignance diseases (MD), including 11 lymphoid and 19 myeloid diseases, and 36 had thalassemia major (TM). Median age was 12 (range; 2-13) and 8 (3-17) years in the MD and TM group, respectively. Median follow-up time was 13 (7-32) and 19 (2-25) months, respectively. Conditioning (Regimen CT-13) included Cyclophosphamide on day-8 to -7, Busulfan on day-6 to -4, Fludarabine on day-6 to -2 and Thiotepa on day-3. Hap-SC was infused on day 0. GVHD prophylaxis consisted of Cyclophosphamide on day+3 to +4. UCB was infused on Day+6. Mycophenolate mofetil and Tacrolimuswas started on day+6 for GVHD prophylaxis. For 26 TM patients transplanted since 2014, they received identical regimen except with the additional Thymoglobulin on day -11 to -9 (Regimen CT-14). Results The chimerism status at last follow-up was Hap-SC, UCB, mixed stem cells (MSC) and rejection in 20, 9, 1 and 0 patient in the MD group; and 16, 14, 3 and 3 patients in the TM group. Interesting, the initial chimerism on day+28 in the TM group was Hap-SC, UCB and MSC engrafted in 15, 7 and 12 patients, respectively. Thus, the MSC was not stable in TM patients; UCB typically became dominant overtime instead of the initial majority from hap-SC (Fig. 1). In the MD group, the time to neutrophil >= 0.5x109/L, platelet >=20 x109/L and hemoglobin >=80 g/L was day+18 (14-36), +10.0 (6-51) and +7 (1-20) in the final hap-SC engrafted group; and+30 (22-35), +25 (1-64) and +7 (3-28) in the final UCB engrafted group. Overall survive (OS), disease-free survive (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were 75.6%, 64.3%, 24.7£¥ and 13.7%, respectively, in all 30 MD patients; and 79.3%,73.8%,15.5% and 12.3% (Fig.2), respectively, in the 25 cases with complete remission (CR) at the time of transplantation. The corresponding data were 89% vs. 88.9%£¬65.0% vs. 77.8%£¬31.1 % vs.12.5% and 10.3% vs.11.1%£¨p>0.05 in all pairs), respectively, in hap-SC and UCB engrafted groups. Donor carrying KIR centromeric B motif was associated with reduced RI (10 % vs. 33.9%). In TM group, OS, thalassemia free survive (TFS), rejection and transplant-related mortality were 91.2%, 85.7%, 5.6% and 8.8%, respectively in all 36 patients. Impressively, all of the 26 patients who received the newer CT-14 protocol were alive without TM (Fig. 2). 7/10 UCB carrying KIR centromeric B motif engrafted. In the MD group, 23.3% had grade II-IV and10.0% had III-IV acute GVHD. Grade II, III and IV acute GVHD occurred in 3 patients, respectively, in TM group. One MD patient had severe chronic GVHD (lung) after DLI for relapse. No moderate chronic GVHD occurred in TM groups. Summary The CT-13 regimen resulted in high OS and DFS, especially in CR patients in the MD group. The CT-14 leaded to 100% TFS in thalassemia patients. Acute and chronic GVHD were acceptable. Donor carrying centromeric B motif promoted engraftment and reduced RI. A multicenter study should be developed in the future based on our favorable results. Figure 1. Kinetics of mixed chimerism in thalassemia patients Figure 1. Kinetics of mixed chimerism in thalassemia patients Figure 2. Results of malignance diseases in CR status at the time of transplant Figure 2. Results of malignance diseases in CR status at the time of transplant Figure 3. Thalassemia-free survive resulted from regimen CT-14 Figure 3. Thalassemia-free survive resulted from regimen CT-14 Disclosures No relevant conflicts of interest to declare.

Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4257-4264 ◽  
Author(s):  
Smita Bhatia ◽  
Harland N. Sather ◽  
Olga B. Pabustan ◽  
Michael E. Trigg ◽  
Paul S. Gaynon ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Brain Tumors ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Childhood All ◽  
Second Neoplasms ◽  
Increased Risk ◽  
The Impact

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

scholarly journals Association between Sociodemographic, Clinical and Immunophenotypic Variables with Disease Relapse and Survival at 12 Months, in Patients with B-Cell Acute Lymphoblastic Leukemia Treated at a Colombian University Hospital

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4380-4380
Author(s):  
Luis Antonio Salazar ◽  
Sandra Vanesa Rios ◽  
Angela María Peña ◽  
Maria Luna-Gonzalez ◽  
Mario Andrés Arenas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Survival Function ◽  
Advisory Board ◽  
Overweight And Obesity ◽  
University Hospital ◽  
The Impact

Abstract INTRODUCTION Acute lymphoblastic leukemia (ALL) is a clonal hematopoietic disorder that originates from B or T lymphoid progenitors. It affects more frequently children, but prognosis is worse in adults. ALL has a high incidence in Hispanics (Swords R et al. Blood Cancer J. 2016) and is important to identify baseline clinical, sociodemographic, and cytogenetic characteristics in these patients that are relevant for relapse free and overall survival. Reports of Hispanic patients with ALL outsides of the U.S.A are scare but are important to further characterize the impact of this disease in minority populations. OBJETIVE To describe the association between sociodemographic, clinical and immunophenotypic variables with 12-month relapse free survival (RFS) and overall survival (OS) in patients diagnosed and treated for ALL in a Colombian university hospital (FOSCAL). MATERIALS AND METHODS This is a descriptive observational cohort study that included patients older than 18 years with a confirmed diagnosis of ALL treated in a tertiary university hospital between 2013-2020 and that had at least 12 months follow-up after starting treatment. Baseline sociodemographic, clinical, laboratory and immunophenotypic data were collected. Bivariate analyses of both relapse and mortality cumulative incidences at 12 months, with relative risks (RR) and their 95% Confidence intervals were performed, using either chi-square or Fischer exact test when needed. In a second term, bivariate survival analyses through Kaplan-Meier survival function and Hazard ratios were evaluated, using Cox proportional hazards as the main statistical test. RESULTS Among 128 of include patients, the median age at diagnosis was 34 years (range 0-89 years), 54% were men, 6.2% had type 2 Diabetes Mellitus (T2DM), most had an ECOG PS of 0 (72.7%), 31.8% had splenomegaly, 12% had hepatomegaly and 47% presented without organomegalies. The proportion of patients with overweight and obesity were 26.3% and 22.2% respectively. At diagnosis 80.5% and 8.8% of patients had high risk and standard risk ALL, respectively Forty-eight patients had a FAB classification with 58% being ALL-2 and most of the were unclassified. Most cases (81%) had B-cell immunophenotype, with 55% being pre-B-cell and 32% mature B-cell. Twelve percent of patients were Ph+ B-ALL. At 12 months, the proportion of mortality was 34.4%. Most of the patients (83%) did not have major co-morbidities, however patients with T2DM had a significantly inferior survival at 12 months, HR: 3.68 (95%CI 1.54-8.8 P=0.003), as patients older than 35 years (HR: 2.15, 95%CI: 1.14-4.0, P=0.017) (Table 1). CONCLUSIONS Colombian patients with B-cell ALL have similar clinical, immunophenotypic and cytogenetic (Ph+ prevalence) characteristics as seen in other international cohorts. In our cohort patients older than 35 years and subjects with T2DM had inferior survival at 1 year. Further analyses of socioeconomic factors, molecular features and response to specific regimens are needed to have a better understanding of Colombian B-ALL patients. Figure 1 Figure 1. Disclosures Salazar: Amgen: Research Funding. Peña: Amgen: Research Funding. Sandoval-Sus: BMS: Other: Advisory Board, Speakers Bureau; SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board. Sossa: Amgen: Research Funding.

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