Minimal residual disease–based long‐term efficacy of reduced‐intensity conditioning versus myeloablative conditioning for adult Philadelphia‐positive acute lymphoblastic leukemia

Cancer ◽  
2018 ◽  
Vol 125 (6) ◽  
pp. 873-883 ◽  
Author(s):  
Jae‐Ho Yoon ◽  
Gi June Min ◽  
Sung‐Soo Park ◽  
Young‐Woo Jeon ◽  
Sung‐Eun Lee ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Reduced Intensity Conditioning ◽  
Myeloablative Conditioning ◽  
Term Efficacy ◽  
Minimal Residual ◽  
Reduced Intensity

scholarly journals Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000)

2018 ◽  
Vol 36 (3) ◽  
pp. 244-253 ◽  
Author(s):  
Martin Schrappe ◽  
Kirsten Bleckmann ◽  
Martin Zimmermann ◽  
Andrea Biondi ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Cumulative Incidence ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Young Patients ◽  
Disease Free Survival ◽  
Standard Risk ◽  
Minimal Residual ◽  
Reduced Intensity

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.

scholarly journals Relationship between minimal residual disease and outcome in adult acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5251-5256 ◽  
Author(s):  
J Brisco ◽  
E Hughes ◽  
SH Neoh ◽  
PJ Sykes ◽  
K Bradstock ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Marrow Cell ◽  
Leukemic Cells ◽  
Chain Gene ◽  
First Remission ◽  
Minimal Residual

In children with acute lymphoblastic leukemia (ALL), the level of minimal residual disease (MRD) at the end of induction strongly predicts outcome, presumably because it measures both drug sensitivity and the number of leukemic cells requiring elimination. Children with high levels (> 10(-3) leukemic cells per marrow cell) nearly always relapse, whereas those with low levels (<2 x 10(-5)) seldom do. However, the importance of MRD in adult ALL is unclear. We studied 27 patients aged 14 to 74 who were treated with a standard protocol and who attained morphological remission. MRD in the marrow at first remission was quantified by using the polymerase chain reaction (PCR), with the rearranged immunoglobulin heavy chain gene as a molecular marker. Levels of MRD varied from 3 x 10(-1) to <7 x 10(-7). The probability of long-term relapse-free survival was significantly related to the level of MRD and only one of nine patients with MRD >10(- 3) did not relapse. For patients who did relapse, there was an inverse relationship between MRD level and the length of remission. Overall, MRD in adults in whom a translocation had not been identified was significantly higher than in comparably-treated children, suggesting that ALL in adults is more drug-resistant than in children.

Unrelated Cord Blood Transplantation (UCBT) in Adult and Pediatric Acute Lymphoblastic Leukemia: Impact of Minimal Residual Disease on Relapse and Survival,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4114-4114
Author(s):  
Veronika Bachanova ◽  
Michael J Burke ◽  
Claudio Brunstein ◽  
Michael R Verneris ◽  
Qing Cao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Relative Risk ◽  
Cord Blood ◽  
Minimal Residual Disease ◽  
Cumulative Incidence ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Myeloablative Conditioning ◽  
Minimal Residual

Abstract Abstract 4114 Background: Umbilical cord blood (UCB) has become a valuable alternative source of stem cells for patients with high risk acute lymphoblastic leukemia (ALL) lacking a matched sibling donor. Data on the efficacy of transplant outcomes after UCB in ALL are limited, particularly for the adult population. Methods: We report the outcomes of 143 patients (74 children <18 years and 68 adults) with ALL who received UCBT at University of Minnesota between 1999–2010. Most had precursor-B ALL (n=87 [61%]), Philadelphia positive ALL (Ph+; n=41 [29%] and T cell ALL (n=15 [10%]). All except 7 patients were in complete remission (CR1: n=59 [41%] or CR2/CR3: n=77 [54%]). Most adults received double UCB grafts (adult =90% vs. children =27%, p=0.01) with HLA locus matching of 4/6 and 5/6 in 65% and 28% of adults vs. 29% and 53% of children (p=0.01). 86 had an assessment of Minimal Residual Disease (MRD) prior to UCBT using 4 to 6 color flow-cytometric analysis and MRD was based on prior (diagnostic) immunophenotype and according to published standards. Ten patients had MRD detected immediately prior to UCBT (2 patients were in CR1, 7 in CR2, 1 in CR3) and 76 patients were MRD-negative. Most patients (82%) received myeloablative conditioning (cyclophosphamide 120 mg/kg, fludarabine 75mg/m2 and total body irradiation (TBI) 1200–1320cGy). Non-myeloablative conditioning (cyclophosphamide 50mg/kg, fludarabine 200mg/m2 and TBI 200cGy was given to patients above 45 years (n=18 [13%]) and in those with poor fitness (n=8 [5%]). All patients received cyclosporine (day −3 to day +180) and mycophenolate mofetil ( day −3 to day +45) post-HCT. Results: The cumulative incidence of neutrophil engraftment by day 42 was 97% (95%CI 92–99%). Six months platelet engraftment was 71% (95%CI 67–85%), 48% (95% CI 32–64%) and 84% (95%CI 58–100%); p<0.01) for patients ≤18 years, 19–45 and >45 years of age, respectively. With a median follow-up of 3.9 years (0.5–11.8 years), the 3-year leukemia-free survival (LFS) and overall survival (OS) was 47% (95%CI 38–55%) and 49% (95%CI 40–57%) with trend to better OS in children (Table). Cumulative incidence of relapse at 1 year was 17% (95%CI 11–23%) and the relative risk tended to lower rates in adults following MA vs NMA conditioning (7% [95%CI 0–14% vs 21% [95%CI 5–37%]; p=0.19). In univariate analysis age, disease status (CR1 vs CR2/CR3 vs. non CR), disease group (pre-B ALL, Ph+ALL, T-ALL) or time to transplant had no impact on relapse rate. Treatment-related mortality at 1 year was higher in adult patients aged 18–45 years (46% [95%CI 31–61%]) compared to children (19% [95%CI 10–28%]) or older patients who received NMA conditioning regimen (TRM 5% [95%CI 0–15%]; p<0.01). Patients with MRD detected immediately prior to UCBT had a higher relative risk of relapse at 2 years (30% [95%CI 4–56%]) and lower LFS (30% [95%CI 7–58%]) compared to MRD- group (16% [95%CI 8–25%]; p=0.05 and 61% [95%CI 49–70%]; p=0.05); respectively. Conclusion: UCBT expands the options for patients with ALL and offers potent protection from post-transplant relapse. Our results indicate that novel strategies in UCB HCT for ALL should focus on decreasing TRM in adult patients receiving myeloablative conditioning and improving leukemia control to induce a MRD- state pre- transplant. Disclosures: No relevant conflicts of interest to declare.

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