More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling

Bader, Peter; Salzmann‐Manrique, Emilia; Balduzzi, Adriana; Dalle, Jean‐Hugues; Woolfrey, Ann E.; Bar, Merav; Verneris, Michael R.; Borowitz, Michael J.; Shah, Nirali N.; Gossai, Nathan; Shaw, Peter J.; Chen, Allen; Schultz, Kirk R.; Kreyenberg, Hermann; Maio, Lucia Di; Cazzaniga, Giovanni; Eckert, Cornelia; Velden, Vincent H.J. van der; Sutton, Rosemary; Lankester, Arjan C.; Peters, Christina; Klingebiel, Thomas; Willasch, André; Grupp, Stephan A.; Pulsipher, Michael A.

doi:10.1182/bloodadvances.2019000449

Cited by 85 publications

(107 citation statements)

References 52 publications

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“…Based on its rarity, the prognosis of patients with neonatal ALL is guarded [ 9 , 10 ]. Treatment of this patient was guided by PCR-based measurements of MRD with the aim to achieve a state of <10 (–4) MRD [ 17 , 18 ] prior to the carefully planned allogeneic stem cell transplantation from an unrelated donor matched at 10/10 loci .…”

Section: Discussionmentioning

confidence: 99%

Neonatal Acute Lymphoblastic Leukemia with t(9;11) Translocation Presenting as Blueberry Muffin Baby: Successful Treatment by ALL-BFM Induction Therapy, Allogeneic Stem Cell Transplantation from an Unrelated Donor, and PCR-MRD-Guided Post-Transplant Follow-Up

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Neonatal Acute Lymphoblastic Leukemia with t(9;11) Translocation Presenting as Blueberry Muffin Baby: Successful Treatment by ALL-BFM Induction Therapy, Allogeneic Stem Cell Transplantation from an Unrelated Donor, and PCR-MRD-Guided Post-Transplant Follow-Up

et al. 2020

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“…With the increased availability of MRD and the recognition of its prognostic utility, persistent MRD is increasingly used as an indication for transplantation. 22,23 The AIEOP-BFM ALL 2000 trial stratified children with persistent MRD ≥10 À3 at day 78 of therapy to HSCT, but found no statistically significant difference in DFS between HSCT and chemotherapy alone ( Table 1). 24 The Nordic Society of Paediatric Haematology and Oncology (NOPHO) cooperative group used MRD >5% at EOI or persistent MRD ≥10 À3 after 3 months of therapy as a potential indication for transplant on the NOPHO ALL-2000 trial and allocated these patients to intensified chemotherapy and HSCT on the subsequent ALL2008 trial.…”

Section: Persistent Mrdmentioning

confidence: 99%

“…26 Nevertheless, HSCT outcomes are also affected by persistent MRD, but these studies measure MRD later, primarily in the peritransplant period. MRD that remains detectable at a level of 10 À3 or 0.1% pre-HSCT increases the risk of relapse, 23,27 prompting several groups to incorporate intensive HR chemotherapy blocks before HSCT. Although the clearance or reduction of MRD to a low level before HSCT may improve DFS, data on MRD reduction are limited, and these blocks are associated with a high rate of grade 3 to 4 toxicities, notably infections in two-thirds of patients.…”

Section: Persistent Mrdmentioning

confidence: 99%

“…28 Finally, post-HSCT MRD was more predictive of relapse risk on a multicenter observational study. 23 It is not clear whether the level of MRD itself is prognostic, or if MRD is a marker of the underlying leukemia biology.…”

Section: Persistent Mrdmentioning

confidence: 99%

“…Although HSCT is often considered for patients with anticipated poor survival with chemotherapy alone, relevant to this population, detectable MRD at the time of HSCT has been consistently associated with an increased risk of relapse, as is MRD post-HSCT. 23,25,27,40,41 Further intensification of chemotherapy to decrease or eliminate MRD and HSCT itself are not without significant risk of morbidity and mortality. 3,22,28,42 Therefore, the possibility of durable remission without consolidative HSCT is one aim of an ongoing trial developed by the COG and Novartis.…”

Section: Aall1721/cassiopeiamentioning

confidence: 99%

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CAR T cells vs allogeneic HSCT for poor-risk ALL

Diorio

Maude

2020

Hematology

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For subgroups of children with B-cell acute lymphoblastic leukemia (B-ALL) at very high risk of relapse, intensive multiagent chemotherapy has failed. Traditionally, the field has turned to allogeneic hematopoietic stem cell transplantation (HSCT) for patients with poor outcomes. While HSCT confers a survival benefit for several B-ALL populations, often HSCT becomes standard-of-care in subsets of de novo ALL with poor risk features despite limited or no data showing a survival benefit in these populations, yet the additive morbidity and mortality can be substantial. With the advent of targeted immunotherapies and the transformative impact of CD19-directed chimeric antigen receptor (CAR)–modified T cells on relapsed or refractory B-ALL, this approach is currently under investigation in frontline therapy for a subset of patients with poor-risk B-ALL: high-risk B-ALL with persistent minimal residual disease at the end of consolidation, which has been designated very high risk. Comparisons of these 2 approaches are fraught with issues, including single-arm trials, differing eligibility criteria, comparisons to historical control populations, and vastly different toxicity profiles. Nevertheless, much can be learned from available data and ongoing trials. We will review data for HSCT for pediatric B-ALL in first remission and the efficacy of CD19 CAR T-cell therapy in relapsed or refractory B-ALL, and we will discuss an ongoing international phase 2 clinical trial of CD19 CAR T cells for very-high-risk B-ALL in first remission.

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Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia

Brown

et al. 2021

JAMA

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197

198

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IMPORTANCE Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile.OBJECTIVE To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high-and intermediate-risk first relapse of B-ALL. DESIGN, SETTING, AND PARTICIPANTSThis trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669).INTERVENTIONS All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. MAIN OUTCOME AND MEASURESThe primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. RESULTS Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group.CONCLUSIONS AND RELEVANCE Among children, adolescents, and young adults with high-and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpret...

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More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling

Abstract: Key Points Low or nondetectable MRD pre-HCT leads to similar outcomes, suggesting that MRD negativity is not an absolute prerequisite for HCT. MRD post-HCT is more important than pre-HCT, and monitoring with sensitive techniques can detect very high-risk patients early.

Cited by 85 publications

References 52 publications

Neonatal Acute Lymphoblastic Leukemia with t(9;11) Translocation Presenting as Blueberry Muffin Baby: Successful Treatment by ALL-BFM Induction Therapy, Allogeneic Stem Cell Transplantation from an Unrelated Donor, and PCR-MRD-Guided Post-Transplant Follow-Up

Neonatal Acute Lymphoblastic Leukemia with t(9;11) Translocation Presenting as Blueberry Muffin Baby: Successful Treatment by ALL-BFM Induction Therapy, Allogeneic Stem Cell Transplantation from an Unrelated Donor, and PCR-MRD-Guided Post-Transplant Follow-Up

CAR T cells vs allogeneic HSCT for poor-risk ALL

Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia

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