A Second Infusion (Early Reinfusion) of Tisagenlecleucel in Children and Young Adults With B-Cell Acute Lymphoblastic Leukemia(B-ALL)

Phase II Open Label Multicenter Study of Early REinFusion of Tisagenlecleucel to Promote DUrable B-CEll ApLasia in Pediatric and Young Adult Patients With Relapsed/Refractory CD19-Positive B-Cell Acute Lymphoblastic Leukemia (REFUEL)

The researchers are doing this study to see if early reinfusion of tisagenlecleucel can keep participants in B-CEll ApLasia at 6 months after their first infusion. The researchers will also look at the safety of early reinfusion and how effective it is at treating B-ALL.

Study Overview

• Status: Active, not recruiting
• Conditions: B-cell Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: Tisagenlecleucel

Detailed Description

Prior to initial tisagenlecleucel cell infusion, lymphodepleting chemotherapy (LDC) is required with standard dosing cyclophosphamide and fludarabine as per standard-of-care (fludarabine 30mg/m^2 /dose x 4 doses and cyclophosphamide 500mg/m^2 /dose x 2 doses). Dose adjustments based off ideal body weight (IBW) and/or per institutional guidelines are allowed. LDC should be completed 2 to 14 days prior to the first tisagenlecleucel infusion. LDC may be repeated in cases where tisagenlecleucel has been delayed by more than 4 weeks. No additional LDC will be given prior to the early reinfusion.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles (Data Collection Only)
    • Stanford, California, United States, 94305
      • Stanford University (Data Collection Only)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado (Data Collection Only)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University (Data Collection Only)
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center (Data Collection Only)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with R/R B-ALL who have received commercial tisagenlecleucel and have (an) additional dose(s) available for early reinfusion
• History of CD19 expressing (in peripheral blood or bone marrow by flow cytometry) BALL prior to tisagenlecleucel infusion
• Peripheral blood B-cell aplasia (BCA) within 14 days prior to reinfusion (See section 13.8: B-cell aplasia will be defined as peripheral blood (PB) absolute B lymphocyte count ≤ 50/μL. If BCA evaluation is repeated at any timepoint prior to reinfusion, it must be negative to proceed with reinfusion
• Minimal residual disease negative complete remission (CR/CRi) in bone marrow within 14 days prior to reinfusion, including resolution of extramedullary disease

• Patients with tisagenlecleucel that is deemed out of specification (OOS) will be permitted on this protocol if the reason for OOS is deemed to not impact the toxicity and efficacy profile of CAR T cell therapy

  °Reasons for product being OOS include cell viability < 80%, total nucleated cell count <2 × 10^9 in leukapheresis product, failed interferon-γ release assay, leukapheresis product collected >9 months prior, and determination of residual beads >50 beads per 3 × 10^6 cells

• Patients age: < 26 years at time of first tisagenlecleucel order placement

• Recovered from severe toxicities following initial dose of tisagenlecleucel

  • CRS
  • Neurotoxicity/ICANS

• Adequate organ function at time of treatment is required and is defined:

  • Hepatic: Serum bilirubin ≤ 2 mg/dL, unless benign congenital hyperbilirubinemia
  • Hepatic: AST and ALT < 5x the upper limit of normal for age, unless thought to be disease-related
  • Renal: Serum creatinine <1.5x normal for age. If serum creatinine is outside the normal range, then CrCl > 60 mL/min/1.73m2 (calculated or estimated) or GFR (mL/min/1.72m2 ) >55% of predicted normal for age

Age Mean GFR +/-SD (mL/min/1.73 m2)

• 1 week 40.6 + / - 14.8
• 2 - 8 weeks 65.8 + / - 24.8
• > 8 weeks 95.7 +/- 21.7
• 2 - 12 years 133 +/- 27
• 13 - 21 years (males) 140 +/- 30

• 13 - 21 years (females) 126.0 + / - 22.0 Abbreviations: GFR, glomerular filtration rate; SD, standard deviation. Greater than 2 years old: Normal GFR is 100 mL/ min. Infants: GFR must be corrected for body surface area.

  • Cardiac: LVEF ≥ 50% by multi-gated acquisition scan (MUGA), resting echocardiogram, or cardiac magnetic resonance imaging (MRI) within 6 weeks of screening
  • Pulmonary: Oxygen saturation as recorded by pulse oximetry of ≥ 90% on room air

• Adequate performance status:

  • Age ≥ 16 years: ECOG ≤ 1 or Karnofsky > 60% at treatment
  • Age < 16 years: Lansky > 60% at treatment
• Patient must be enrolled on institutional CIBMTR reporting protocol for immune effector cells (IEC)/CAR T cells
• Each patient must be willing to participate as a research subject, and patient or legal guardian must sign an informed consent form, along with patient assent if between 7 to 17 years of age. Legally authorized representatives of adult patients with impaired decision-making capacity will also be able to sign consent.

Exclusion Criteria:

• Greater than 60 days from first tisagenlecleucel infusion
• Ongoing severe toxicities from initial CAR T cell infusion
• Received non-standard lymphodepleting chemotherapy (LDC) prior to initial tisagenlecleucel dose

• Standard LDC is defined as:

  • Fludarabine 30mg/m^2/dose x 4 doses
  • Cyclophosphamide 500mg/m^2/dose x 2 doses
• Loss of BCA at any timepoint prior to reinfusion
• Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
• Patient/parent/guardian unable to give informed consent or unable to comply with the treatment protocol
• Pregnant or lactating women; women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by flow cytometry on two consecutive tests.
• Sexually active males, unless they are willing to use a condom during intercourse while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by flow cytometry on two consecutive tests.
• Other uncontrolled, symptomatic, intercurrent illness including but not limited to infection, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject
• Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tisagenlecleucel; Patients will receive reinfusion of tisagenlecleucel on day +30-60 after their initial infusion if meeting eligibility criteria. Tisagenlecleucel is an autologous cellular immunotherapy product that is comprised of CD3+T cells that have undergone ex vivo T cell activation, gene modification, expansion, and formulation in infusible cryomedia.	Biological: Tisagenlecleucel; Tisagenlecleucel will be infused based on institutional guidelines. Reinfusion of tisagenlecleucel will occur 30-60 days following the first dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
decrease the loss of peripheral BCA rate	below 10% (from 26% to 9%)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number and percentage of toxicities with early reinfusion of CAR T cells	CTCAE Version 5 will be utilized for toxicity evaluation	1 year

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Kevin Curran, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2022
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: July 13, 2022
• First Submitted That Met QC Criteria: July 13, 2022
• First Posted (Actual): July 15, 2022

Study Record Updates

• Last Update Posted (Actual): February 4, 2026
• Last Update Submitted That Met QC Criteria: February 3, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Tisagenlecleucel; Relapsed/Refractory CD19-Positive B-Cell; REinFusion; REFUEL; 22-220
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Immune System Diseases; Infections; Virus Diseases; Neoplasms by Histologic Type; DNA Virus Infections; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Epstein-Barr Virus Infections; Herpesviridae Infections; Tumor Virus Infections; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Recurrence; Burkitt Lymphoma; Antineoplastic Agents, Immunological; Antineoplastic Agents; tisagenlecleucel
• Other Study ID Numbers: 22-220

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No