Outcomes of Adolescents and Young Adults Compared with Children with Acute Leukemia after Single-Unit Unrelated Cord Blood Transplantation Using Myeloablative Conditioning without Antithymocyte Globulin

2021 ◽  
pp. 1-11
Author(s):  
Xuhan Zhang ◽  
Huilan Liu ◽  
Changcheng Zheng ◽  
Baolin Tang ◽  
Xiaoyu Zhu ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Single Unit ◽  
Antithymocyte Globulin ◽  
Immune Reconstitution ◽  
Cord Blood Transplantation ◽  
Myeloablative Conditioning ◽  
Platelet Recovery ◽  
Blood Transplantation ◽  
Cell Counts ◽  
Neutrophil Engraftment

<b><i>Background:</i></b> Although the use of cord blood transplantation (CBT) is becoming more frequent in acute leukemia, considering the relationship between the low stem cell dose and graft failure, whether use of CBT for adolescents and young adults (AYAs) is appropriate remains uncertain. <b><i>Methods:</i></b> A retrospective registry-based analysis of clinical outcomes and immune reconstitution was conducted for 105 AYAs and 187 children with acute leukemia who underwent single-unit CBT using myeloablative conditioning (MAC) without antithymocyte globulin (ATG). <b><i>Results:</i></b> Outcomes were similar between AYAs and children, except for nonrelapse mortality (NRM) and recovery rates of neutrophils and platelets. The 30-day cumulative incidence of neutrophil engraftment was similar between AYAs and children, but children had faster rates of neutrophil and platelet recovery than AYAs. The median time to neutrophil engraftment was earlier in children than in AYAs (AYAs, 19 days, 95% confidence interval [CI] 17.3–21.7; children, 16 days, 95% CI 13.1–19.5, <i>p =</i> 0.00003). The incidence of platelet recovery on day 120 was higher in children than in AYAs (AYAs, 80%, 95% CI 71–81%; children, 88%, 95% CI 82–92%, <i>p =</i> 0.037). CD34<sup>+</sup> cell dose was the only independent factor influencing both neutrophil and platelet recovery. The cumulative incidence of NRM at 2 years was higher among AYAs than among children (AYAs, 27.5%, 95% CI 20–37%; children, 15%, 95% CI 10–21%, <i>p =</i> 0.008). Conditioning regimen was an independent factor influencing NRM. With respect to immune reconstitution, natural killer cell counts quickly recovered to normal levels 1-month post-CBT in both children and AYAs. CD8<sup>+</sup> T-cell counts were higher in children than in AYAs at 1 and 3 months post-CBT. CD4<sup>+</sup> T-cell counts were similar in both children and AYAs after CBT. <b><i>Conclusion:</i></b> AYAs with acute leukemia have outcomes of single-unit CBT using MAC without ATG that are as good as those of children. Thus, single-unit CBT using modified MAC without ATG is an acceptable choice for both AYAs and children who do not have a suitable donor.

Intensified Myeloablative Conditioning Regimen without Antithymocytic (ATG) Results in Superior Patient Outcome Compared to Myeloablative Conditioning Regimen for Single-Unit Umbilical Cord Blood Transplantation in Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5837-5837
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Yue Wu ◽  
Changcheng Zheng ◽  
Baolin Tang ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cumulative Incidence ◽  
Single Unit ◽  
Hematological Malignancies ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Blood Transplantation ◽  
Group A ◽  
Neutrophil Engraftment

Abstract The superiority and safety of strengthening conditioning regimen for single- unit unrelated cord blood transplantation (sUCBT) in hematological malignancies remain controversial. We retrospectively analyzed the clinical data of 251 hematological malignancies undergoing sUCBT from Apr 2000 to Dec 2014 at Department of hematology in Anhui Provincial Hospital. Out of the 251 patients, 216 received the intensified myeloablative conditioning regimen (IMCR), and 35 received the myeloablative conditioning regimen (MCR). We evaluated the effect of IMCR without using Antithymocyte globulin (ATG) on patient outcomes. The cumulative incidence of myeloid and platelet engraftment of the IMCR group was significantly higher than that in the MCR group (96.98% vs. 82.81%, 85.89% vs. 51.79%, P=0.000 and 0.003, respectively). Corresponding incidences of transplantation-related mortality (TRM) by 180 days in the IMCR group and the MCR group were 19.50% vs. 41.67% (P=0.003), respectively. There were no differences in the incidence of grade II to IV acute GVHD (aGVDH), grade III to IV aGVHD and 2-year cumulative incidence of relapse. Up to Dec. 2015, with a median follow-up of 30 months, the estimated 3-year overall survival and disease- free survival in the IMCR group were both significantly higher than that of the MCR group (64.8% vs. 35.5%, 61.6% vs. 35.5%, P=0.000 and 0.001, respectively). This study is the first to show the superiority of intensified myeloablative regimen to conventional myeloablative regimen.A large-scale prospective study was needed. (A) (B) Figure 1 The cumulative incidence of neutrophil and platelet engraftment of the IMCR group and MCR group. (A)The cumulative incidence of neutrophil engraftment of the IMCR group was predominantly higher than that in the MCR group(96.98% vs. 82.81%, P=0.000). (B)The cumulative incidence of platelet engraftment of the IMCR group was also higher than that in the MCR group(85.89% vs. 51.79%, P=0.003). Figure 1. The cumulative incidence of neutrophil and platelet engraftment of the IMCR group and MCR group. (A)The cumulative incidence of neutrophil engraftment of the IMCR group was predominantly higher than that in the MCR group(96.98% vs. 82.81%, P=0.000). (B)The cumulative incidence of platelet engraftment of the IMCR group was also higher than that in the MCR group(85.89% vs. 51.79%, P=0.003). Figure 2 Comparison of the incidence of 3-year OS between the IMCR group and the MCR group.The incidence of 3-year OS of the IMCR group is predominantly higher than that of the MCR group(62.4% vs. 35.5%,P=0.001). Figure 2. Comparison of the incidence of 3-year OS between the IMCR group and the MCR group.The incidence of 3-year OS of the IMCR group is predominantly higher than that of the MCR group(62.4% vs. 35.5%,P=0.001). Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

High Rate of Engraftment and Low Regimen-Related Toxicity Using Fludarabine, Melphalan and Thiotepa Conditioning for Unrelated Donor Cord Blood Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4414-4414
Author(s):  
Stefan O Ciurea ◽  
Partow Kebriaei ◽  
Issa F Khouri ◽  
Muzaffar H. Qazilbash ◽  
Roy B Jones ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Adult Patients ◽  
High Rate ◽  
Unrelated Donor ◽  
Platelet Recovery ◽  
Blood Transplantation

Abstract BACKGROUND: Cord blood transplantation (CBT) represents an alternative source of stem cells for adult patients who lack a matched sibling or unrelated donor. However, the optimal type and intensity of the preparative regimen for patients receiving a CBT is not clear. We hypothesized that a conditioning regimen consisting of fludarabine, melphalan and thiotepa will be associated with an acceptable rate of engraftment and treatmentrelated mortality in patients receiving a CBT. METHODS: 37 patients, median age 31 years (2–57) and a median weight of 73kg, were treated between 8/2003 and 5/2008. All had advanced hematologic malignancies (24 with acute leukemia, 12 with lymphoma and one with CLL) At the time of transplant, 21 pts (57%) were in complete remission (CR) (first CR=20%) and 16 had relapsed/refractory disease. Grafts consisted of double (29 pts) or single (8 pts) CB units. Cytogenetics for patients with acute leukemia were poor in 11, intermediate in 9, good in 1 and unknown in 3 pts. Donor recipient HLA matching was (intermediate resolution class I HLA A and B and high-resolution DRB1): 3/6 (n=1, 1.5%), 4/6 (n=47, 71.2%) and 5/6 (n=18, 27.3%) alleles (n=66 units). Median total nucleated cell count was 1.8×107/kg (range 1–5.8). Nineteen patients received ex-vivo expanded units. The conditioning regimen consisted of melphalan 140 mg/m2 on day -8, thiotepa 10 mg/m2 on day -7, fludarabine 160 mg/m2 over 4 days on days -6, -5, -4, -3, and rabbit ATG 1.25 mg/kg on day -4 and 1.75 mg/kg on day -3 (FMT). Patients with CD 20+ lymphoid malignancies also received rituximab 375mg/m2 on day -9 (n=8, 22%). GVHD prophylaxis was tacrolimus and mini-methotrexate in 23 (62%) and tacrolimus and mycophenolate in 14 pts (38%). RESULTS: 36 patients (97%) were evaluable for engraftment. 1 patient died within 30 days due to progressive leukemia. 34/36 patients (95%) engrafted neutrophils and had hematopoietic recovery with 100% cord blood-derived cells. At day 30, of the 29 patients who received a double CBT, 75% had chimerism derived entirely from one donor while 25% had mixed donors chimerism. Neutrophil recovery to ANC &gt;0.5 × 10e9/l occurred after a median of 21 days (range 6–45) and platelet recovery to &gt;20 × 10e9/l after a median of 37 days (range 26–134, N=24; 67%). 32/37 pts (87%) were in CR after transplant with 16 surviving after a median follow-up of 12.1 months. Thirteen patients (36%) developed gr II–IV aGVHD (gr III–IV aGVHD in 5 patients, 14%), and 13 of 32 patients had cGVHD (40%), with the majority experiencing extensive GVHD. 11 patients (29.7%) relapsed after a median of 7 months post transplant and 12 died of nonrelapse causes. Day-100 treatment-related mortality in this heavily pre-treated population was 10%. Overall, causes of death included disease relapse (n=9), infections (n=6), organ failure (n=3), pulmonary hemorrhage (n=1) and GVHD (n=2). CONCLUSIONS: The FMT regimen was sufficiently immunosuppressive to support high rate of engraftment with acceptable TRM in heavily pre-treated adult patients with advanced hematologic malignancies undergoing CBT. These results support further evaluation of this regimen in CBT.

Reduced-Intensity Versus Myeloablative Conditioning for Unrelated Cord Blood Transplantation in Adults with Acute Leukemia: A Report from Eurocord, the Acute Leukemia Working Party and the Cord Blood Committee of the Cellular Therapy & Immunobiology Working Party of the European Group for Blood and Marrow Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 155-155
Author(s):  
Frederic Baron ◽  
Ruggeri Annalisa ◽  
Eric Beohou ◽  
Myriam Labopin ◽  
Guillermo Sanz ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cord Blood ◽  
Research Funding ◽  
Cord Blood Transplantation ◽  
Working Party ◽  
Myeloablative Conditioning ◽  
Unrelated Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Unrelated Cord Blood ◽  
Reduced Intensity

Abstract BACKRGOUND. Non-relapse mortality (NRM) is the first cause of treatment failure after unrelated cord blood transplantation (UCBT) following myeloablative conditioning (MAC). In the last decade, reduced-intensity conditionings (RIC) for UCBT have been developed with the aim of reducing NRM and allowing older patients and those with medical comorbidities to benefit from UCBT. The aim of our retrospective registry study was to compare outcomes of acute leukemia (AL) adult patients given UCBT after either RIC or MAC regimens. Regimens were classified as MAC or RIC based on EBMT criteria. PATIENTS AND METHODS. Data from 1352 adult (> 18 yrs) patients with AL (acute myeloid leukemia [AML; n=894] or acute lymphoblastic leukemia [ALL; n=458]) given a first single or double UCBT from 2004 to 2013 at EBMT-affiliated centers were included in this retrospective study. RESULTS. 518 patients were given UCB after RIC, while 834 patients were administered MAC. The most frequently used conditioning regimens combined either TBI, cyclophosphamide and Flu (TCF regimen, given in 22% of MAC vs 75% of RIC recipients, P<0.001), or thiotepa, Bu and Flu (TBF, given in 32% of MAC vs 6% of RIC recipients, P<0.001). In comparison to MAC recipients, RIC recipients were almost 2 decades older (median age 52.5 vs 33.7 yrs, P<0.001), were more often transplanted for AML (80% vs 57%, P=0.001), received more frequently 2 cord blood units (61 vs 32%, P<0.001), received more frequently units with > or = 2 HLA-mismatches (69% vs 58%, P<0.001), received more TNC (median 3.5x10E7 vs 2.9x10E7, P<0.001), and received less frequently ATG in the conditioning (23% versus 57%). Disease status at UCBT was comparable in both groups (51% of patients in CR1 and 17% >CR). Median follow-up for survivors was 25 months. In univariate analyses, in comparison to patients given MAC, RIC recipients had a similar rate of neutrophil engraftment (89.5 vs 89%, P=0.7), and a similar incidence of grade II-IV acute (34% vs 29%, P=0.1) and chronic (22% vs 26%, P= 0.22) GVHD. In contrast, at 2-yr, RIC recipients had a higher incidence of disease relapse (41 vs 24%, P<0.001) but a lower NRM (19 vs 37%, P<0.001), translating to similar leukemia-free survival (LFS, 40% vs 38%, P=0.6) but better overall survival (OS, 47 vs 42%, P=0.01) than MAC recipients (Figure 1). Further, among ALL patients, the use of TCF regimen (n=159) was associated lower NRM (21 vs 40% at 2-yr, P<0.001), lower relapse incidence (24 vs 34%, P=0.07), and better OS (63 vs 34%, P<0.001) and LFS (55 vs 27%, P<0.001). We performed separate multivariate analyses (MVA) for patients with AML and ALL. In MVA for AML patients, the use of RIC regimen was associated with a higher incidence of relapse (HR=1.6, P=0.005) but a suggestion for lower NRM (HR=0.7, P=0.1) translating to similar OS (HR=1.0, P=0.9) and LFS (HR=1.1, P=0.3). Similarly, in MVA for ALL patients, the use of RIC regimen was associated with a higher incidence of relapse (HR=2.0, P=0.002) but a lower NRM (HR=0.6, P=0.04) translating to similar OS (HR=0.8, P=0.2) and LFS (HR=1.1, P=0.5). Further, interestingly, conditioning with TCF-based regimen was associated with a lower incidence of relapse (HR=0.5, P=0.004) translating into better OS (HR=0.6, P=0.013) and LFS (HR 0.6, P=0.002) in ALL patients in MVA adjusted for conditioning intensity (RIC vs MAC). CONCLUSIONS. These data suggest that LFS and OS might be as good with RIC than with MAC in adults AL patients offered UCBT. These observations could serve as basis for future prospective randomized studies. Figure 1. Unadjusted UCBT outcomes in patients transplanted following RIC versus MAC. Figure 1. Unadjusted UCBT outcomes in patients transplanted following RIC versus MAC. Disclosures Milpied: Celgene: Honoraria, Research Funding. Sierra:Amgen: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Mohty:Janssen: Honoraria; Celgene: Honoraria. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand.

Association Between Busulfan First-Dose Pharmacokinetics and Outcome in Children Receiving Myeloablative Busulfan-Based Conditioning Before Unrelated Umbilical Cord Blood Transplantation for Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4143-4143
Author(s):  
Henrique Bittencourt ◽  
Mohamed Aziz Rezgui ◽  
Samira Meziani ◽  
Marie-France Vachon ◽  
Catherine Desjean ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Acute Leukemia ◽  
Toxic Effect ◽  
Drug Monitoring ◽  
Cord Blood Transplantation ◽  
Therapeutic Drug ◽  
Platelet Recovery ◽  
Neutrophil Recovery ◽  
Blood Transplantation ◽  
Related Mortality

Abstract Abstract 4143 Myeloablative unrelated cord blood transplantation (MAC-UCBT) is an alternative to transplant in children with acute leukemia or myelodisplastic syndrome (MDS) when a donor is not available. Intravenous (iv) busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used and is associated with higher EFS, lower transplant-related mortality (TRM) and toxicity. Even if iv Bu has a more predictable bioavailability comparing with oral Bu, there is still an important variation in Bu pharmacokinetics (PK) between patients that may cause treatment failure and toxicity. In order to analyze the impact of PK parameters of the first iv Bu dose on the different outcomes of MAC-UCBT for acute leukemia and MDS, we analyzed 34 consecutive transplants performed in children between dec/2000 and dec/2011. Patients or parents provided an informed consent. Median age at transplant was 5.9 (0.6–19) years, and 19 (56%) were male. There were 20 AML, 2 ALL and 12 MDS. A total of 10 and 12 patients with acute leukemia were transplanted in first remission (CR1), second remission (CR2)/advanced phase of disease, respectively. Thirty-one patients received a single UCBT. Eight, and twelve patients received a 6/6, or 5/6HLA-matched graft. Median infused nucleated cells and CD34+ cells were 5.5 × 10⋀7/kg and 2.1 × 10⋀5/kg, respectively. Cyclosporin A and steroids were used as graft versus host disease (GvHD) prophylaxis for all patients and 33 patients received ATG. Conditioning regimen consisted of first-dose PK-adapted Bu (targeted steady-state concentration - Css - between 600–900 ng/ml) and Cy 200 mg/kg (n=30), Melphalan 135 mg/m2 (n=2) or Cy 120 mg/kg and etoposide 30 mg/kg (n=2). Median follow-up was 36 months. After iv Bu first dose, median Css was 555 ng/ml, AUC was 188,901 min*ng/ml and clearance was 4.61 ml/min/kg. Cumulative incidence (CI) of neutrophil (>0.5×10⋀9/L) at D+60 and platelet recovery (>50×10⋀9/L) at D+150 were both 87%. Median time to neutrophil and platelet recovery was 20 days and 67 days, respectively. There were six primary or secondary graft failure. CI of acute GVHD grade II-IV at D+180 was 16%. There were two cases of VOD. Five-years CI of transplant-related mortality (TRM) was 12%. CI of relapse at 5 years was 25%. Estimated event-free survival (EFS) at 5 years was 49%. Estimated overall survival (OS) at 5 years was 64%. First dose Css significantly influenced neutrophil recovery (100% vs. 70% for Css < and > 600 ng/ml, respectively - P=0.002), TRM (0% vs. 27% for Css < and > 600 ng/ml, respectively - P=0.02), EFS (73% vs. 18% for Css < and > 600 ng/ml, respectively- P<0.001) and OS (82% vs. 43% for Css < and > 600 ng/ml, respectively - P=0.005). There was no influence of Css on the incidence of platelet recovery, grade 2–4 aGVHD or relapse. In conclusion, first dose iv Bu PK seems to be a significant prognostic factor after UCBT for malignancies in children, influencing neutrophil recovery, TRM, EFS and OS. A direct toxic effect of Bu and/or a synergistic toxic effect with Cy might explain the worst outcome when first dose iv Bu has a Css higher than 600 ng/ml. It will be important to validate these results in a multicentre study and also to compare these results with patients that received a fixed dose of Bu. Finally, our data reinforces the importance of Bu therapeutic drug monitoring-guided dosing in pediatric HSCT patients. Disclosures: No relevant conflicts of interest to declare.

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