NGS Monitoring for Acute Lymphoblastic Leukemia

Recruiting at 7 trial locations

Overseen By Nirali N Shah, M.D.

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: National Cancer Institute (NCI)

Disqualifiers: Prior HCT, CNS disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Chimeric antigen receptor T-cell (CART) therapy is a form of immunotherapy which can be used to treat people with relapsed B-ALL. For those who achieve remission after CART alone, it may cure up to 50% of people who receive this therapy. However, for people who relapse after CART, it can be hard to achieve remission again. In patients where CART fails, stem cell transplant (HCT) can be used to prevent relapse and achieve cure. But HCT can cause serious side effects. Better testing is needed to distinguish people who can be cured with CART alone from people who may also need to have HCT. Objective: To see if the use of a series of blood and bone marrow tests at regular intervals can help monitor for B-ALL relapse after CART therapy. Eligibility: People aged 1 to 25 years with B-ALL who have had CART therapy within the past 42 days. They must never have had a blood stem cell transplant; they must also have no measurable blood cancer cells. Design: Participants will visit the clinic every 2 weeks starting 42 days after they receive CART therapy. Each visit will be about the same amount of time as a regular clinic visit. about 8 hours. Participants will have blood drawn for testing on each visit. Bone marrow biopsy/aspirate will be done during 4 of the visits at routine timepoints after CART. A needle will be inserted to draw a sample of tissue from inside the bone in the hip. A small amount of blood and tissue will be tested with ClonoSEQ and to evaluate for normal B-cells side by side with the standard tests. The combined testing may help determine whether participants are eligible for HCT and/or at risk of relapse after CART. Participants will be in the study for 2 years.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the treatment NGS testing, Kymriah, tisagenlecleucel-T, tisa-cel, CART19, CTL-019 for acute lymphoblastic leukemia?

The research highlights that next-generation sequencing (NGS) is a promising tool for monitoring minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL), which is crucial for predicting relapse and improving cure rates. NGS provides detailed genetic information that can guide personalized treatment strategies, making it a valuable component in managing ALL. ^{1 2 3 4 5}

Is NGS testing safe for humans?

The research articles provided do not contain specific safety data for NGS testing in humans, but they focus on its utility and accuracy in detecting genetic variations in acute lymphoblastic leukemia. ^{3 4 5 6 7}

How does NGS monitoring differ from other treatments for acute lymphoblastic leukemia?

NGS (next-generation sequencing) monitoring for acute lymphoblastic leukemia is unique because it uses advanced genetic sequencing to detect minimal residual disease (MRD) at very low levels, which can help identify patients at risk of treatment failure earlier than traditional methods. This allows for more personalized treatment planning, potentially improving outcomes by guiding additional therapies like stem cell transplantation. ^{1 3 6 8 9}

Research Team

Nirali N. Shah

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for children and young adults aged 1 to 25 with B-ALL who have recently undergone CART therapy but haven't had a stem cell transplant. They should be in remission, without measurable cancer cells, and have an identified donor for potential future HCT.

Inclusion Criteria

My leukemia is CD19 positive according to a specific genetic test.

Post-CD19 CART infusion disease status: Are in bone marrow morphologic complete remission and are flow cytometry measurable residual disease (MRD) negative within 42 days post CD19 CART infusion and within 14 days prior to the first on-study intervention; Are NGS MRD negative by tracking sample in the bone marrow within 42 days post CD19 CART infusion and within 14 days prior to the first on-study intervention confirmed by NGS MRD testing; Have an absolute neutrophil count (ANC) > 500 cell/mm^3 without needing growth factor support by 42 days post CD19 CART infusion and within 4 days prior to the first on-study intervention; Received first CD19 (4-1BB) CART within 42 days prior to the first on-study intervention; All participants must have an allogeneic HCT donor identified for potential HCT; Have B-cell aplasia (BCA) post CD19 CART persisting within 14 days prior to the first on-study intervention; Performance of all screening tests prior to day 42 post CD19 CART; The ability of participant or parent/guardian to understand and the willingness to sign a written consent document or participants unable to consent if they are represented by a Legally Authorized Representative (LAR)

I am between 1 and 25 years old.

Exclusion Criteria

I have had a stem cell transplant before.

Co-morbidities precluding myeloablative HCT; Determination of co-morbidities precluding myeloablative HCT will be made by the treating transplant (HCT) physician and documented in the research record

Uncontrolled, symptomatic, intercurrent illness or social situations that would limit compliance with study requirements; Determination of uncontrolled, symptomatic illness or social situation that would limit compliance with the study requirements will be made by the site-PI and documented in the research record

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monitoring

Participants undergo systematic, frequent monitoring to risk stratify for relapse post-CART

2 years

Every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after CART therapy

1 year

Treatment Details

Interventions

• NGS testing

Trial Overview The study tests if regular blood and bone marrow NGS testing after CART therapy can predict relapse in B-ALL patients. It aims to determine the necessity of additional treatments like HCT by monitoring B-cell recovery.

Participant Groups

Group I: 1/Intervention Experimental Treatment 1 Intervention

Systematic, frequent monitoring intervention to risk stratify pts for risk of relapse postCART

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Next-generation sequencing (NGS) has significantly advanced the understanding of acute lymphoblastic leukemia (ALL) by identifying novel molecular entities, which can improve diagnosis, risk stratification, and treatment planning.

Early efforts to use NGS for assessing minimal residual disease (MRD) in ALL show promise, highlighting the potential for personalized medicine approaches in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next-Generation Sequencing in Acute Lymphoblastic Leukemia. Coccaro, N., Anelli, L., Zagaria, A., et al.[2020]

Next-Generation Sequencing (NGS) is becoming an important tool for diagnosing and managing B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but its complexity poses challenges for consistent clinical implementation across different laboratories.

A collaborative study among Spanish centers found that while various NGS panels performed well, each had unique advantages and drawbacks, highlighting the need for standardized analysis and reporting to improve result concordance in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Helpful Criteria When Implementing NGS Panels in Childhood Lymphoblastic Leukemia. Vega-Garcia, N., Benito, R., Esperanza-Cebollada, E., et al.[2020]

The ALLseq next-generation sequencing panel effectively detects a wide range of genetic alterations in acute lymphoblastic leukemia (ALL), demonstrating 100% sensitivity and specificity, making it a reliable tool for clinical use.

This panel can provide clinically relevant information for over 83% of pediatric patients with ALL, aiding in diagnosis, risk assessment, and treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Validation of a Custom Next-Generation Sequencing Panel in Pediatric Acute Lymphoblastic Leukemia. Gil, JV., Such, E., Sargas, C., et al.[2023]

Minimal residual disease (MRD) is a crucial factor in predicting outcomes for acute lymphoblastic leukemia (ALL), and advancements in MRD detection methods have significantly improved cure rates across all age groups.

Next-generation sequencing (NGS) offers enhanced sensitivity and specificity for MRD detection compared to traditional RQ-PCR methods, and it provides valuable insights into the immune cell repertoire, although standardization of the NGS workflow is necessary before it can be widely implemented in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is Next-Generation Sequencing the way to go for Residual Disease Monitoring in Acute Lymphoblastic Leukemia? Kotrova, M., Trka, J., Kneba, M., et al.[2018]

A comprehensive next-generation sequencing (NGS) assay was developed to detect various genetic abnormalities in acute lymphoblastic leukemia (ALL), including somatic mutations and copy number changes, demonstrating its clinical utility in patient evaluation.

The assay effectively identified single nucleotide variations (SNVs) and copy number variations (CNVs) simultaneously, which can simplify testing processes and aid in risk stratification for patients with high-risk mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility of targeted NGS panel with comprehensive bioinformatics analysis for patients with acute lymphoblastic leukemia. Kim, B., Lee, H., Kim, E., et al.[2020]

The study introduces a Vidjil add-on that allows for the analysis of NGS libraries prepared using the EuroClonality-NGS protocol, which is essential for assessing minimal residual disease in acute lymphoblastic leukemia.

Analysis results from Vidjil and ARResT/Interrogate showed a high level of agreement (r = 0.998) and low error rates, indicating that the Vidjil add-on is a reliable tool for processing these specific NGS libraries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vidjil add-on for MRD quantification of samples processed using the EuroClonality-NGS protocol. Giusti, GNN., Ribeiro, AV., Jotta, PY., et al.[2023]

In a study of 158 acute myeloid leukaemia samples, 16 lower-performance amplicons were identified in the TruSight Myeloid Sequencing Panel, including the gene CEBPA, which could affect diagnostic accuracy.

By using a different library preparation method (Nextera XT), researchers successfully increased the read depth for the CEBPA gene, demonstrating a way to improve sequencing results for genes with low performance in standard panels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coverage analysis in a targeted amplicon-based next-generation sequencing panel for myeloid neoplasms. Yan, B., Hu, Y., Ng, C., et al.[2022]

Next-generation sequencing was used to identify leukemia-specific sequences after tisagenlecleucel therapy in patients with acute lymphoblastic leukemia, highlighting its potential for early detection of therapy failure.

Detecting residual disease at levels below one per million cells by day 28 post-therapy was linked to poorer outcomes, suggesting that this method could help identify patients who may need additional treatments like stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rare Sequences Make Sense of CAR T-cell Therapy Outcomes. Ghorashian, S., Bartram, J.[2023]

Next-generation sequencing (NGS) is more sensitive than traditional methods like multiparametric flow cytometry (MFC) and real-time quantitative PCR (RQ-PCR) for detecting minimal residual disease (MRD) in children with acute lymphoblastic leukemia (ALL), identifying MRD in 57.5% of B-ALL and 80% of T-ALL cases after chemotherapy.

In B-ALL patients, having two or more clonal rearrangement sequences before treatment is linked to a higher likelihood of remaining positive for MRD after chemotherapy, indicating that NGS can help identify patients at greater risk for treatment failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical application of next-generation sequencing-based monitoring of minimal residual disease in childhood acute lymphoblastic leukemia. Mai, H., Li, Q., Wang, G., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Next-Generation Sequencing in Acute Lymphoblastic Leukemia. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Helpful Criteria When Implementing NGS Panels in Childhood Lymphoblastic Leukemia. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Design and Validation of a Custom Next-Generation Sequencing Panel in Pediatric Acute Lymphoblastic Leukemia. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Is Next-Generation Sequencing the way to go for Residual Disease Monitoring in Acute Lymphoblastic Leukemia? [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical utility of targeted NGS panel with comprehensive bioinformatics analysis for patients with acute lymphoblastic leukemia. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Vidjil add-on for MRD quantification of samples processed using the EuroClonality-NGS protocol. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Coverage analysis in a targeted amplicon-based next-generation sequencing panel for myeloid neoplasms. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Rare Sequences Make Sense of CAR T-cell Therapy Outcomes. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Clinical application of next-generation sequencing-based monitoring of minimal residual disease in childhood acute lymphoblastic leukemia. [2023]