IRB Study Number 19-1392
Status Recruiting
Phase Phase 2
Location Cleveland Clinic Main Campus
Institutes Taussig Cancer Institute, Pediatric Institute
Description
Primary Objective
- Estimate the 2-year EFS and the 2-year cumulative incidences of relapse and non-relapse mortality in pre-HCT NGS-MRD negative patients with B-ALL undergoing a non-TBI based conditioning regimen.
Exploratory Objectives
Estimate overall survival (OS) following a non-TBI based conditioning regimen in B-ALL patients who are pre-HCT NGS-MRD negative.
Correlate the presence of and level of pre-HCT NGS-MRD in BM samples of B-ALL patients screened for the trial with detectable disease with relapse, EFS, and OS after best available therapy offered by their transplant centers.
Correlate the presence and level of NGS-MRD in BM samples of B-ALL patients pre- and post-HCT with overall and event-free survival (OS, EFS).
Correlate pre- and post-HCT NGS-MRD levels in peripheral blood (PB) and BM samples of B-ALL patients pre- and post-HCT with relapse, OS, and EFS.
Compare NGS-MRD in BM samples of B-ALL patients pre- and post-HCT with multichannel flow cytometry (MFC) for predictive ability for relapse, OS, and EFS.
Assess the effect of acute and chronic GVHD on relapse, EFS, and OS in B-ALL patients with and without the presence of MRD measured by NGS or by MFC.
Screen B-ALL clones at relapse post-HCT to assess whether changes in B-cell clonal rearrangements occur compared to pre-HCT blasts.
Estimate rates of relapse, EFS, and OS in children < 3 undergoing a non-TBI based conditioning regimen for B-ALL and correlate these outcome with flow and NGS-MRD measured pre- and post- HCT.
Correlate the presence and level of NGS-MRD in BM samples of T-ALL and MPAL (mixed phenotype acute leukemia) patients pre- and post-HCT with overall and event-free survival (OS, EFS).
Inclusion Criteria
Pre-HCT NGS-MRD negative
Age ≥ 1 year and ≤ 25 years
Disease status:
a) CR1 indications: B-ALL high-risk in first remission (<5% blasts by morphology pre-transplant) meeting criteria for transplant. Example CR1 indications:
• Primary induction failure (>5% blasts on post-induction BM)
• MRD ≥1% marrow blasts by morphology (or flow cytometry) after induction
• MRD ≥ 0.01% after consolidation
• Hypodiploidy (<44 chromosomes or DNA index <0.81)
• Persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction (e.g. Ph+, Ph- like or others). Notes: CR1: Patients with CNS or testicular disease at time of initial diagnosis should have received the center standard treatment of new diagnosis ALL with CNS or testicular disease and cleared disease. These patients are eligible for the study treatment arm.
b) CR2 indications: B-ALL in second remission (<5% blasts by morphology pre-transplant) meeting criteria for transplant including the following:
Early bone marrow (BM) relapse (≤ 36 month from initiation of therapy of primary diagnosis)
Late BM relapse with MRD ≥ 0.1% by MFC after first re-induction therapy
Ph+ with bone marrow relapse at any time
Early isolated extra-medullary relapse& (<18 month from initiation of therapy of primary diagnosis) other than CNS relapse Notes: & CR2: Patients with adequately (orchiectomy or testicular irradiation as defined by center standard) treated testicular disease will be allowed on the treatment arm of the study.
No prior allogeneic hematopoietic stem cell transplant.
Patients in CR1 or CR2 after blinatumomab treatment.
Patients in CR1 or CR2 after CAR-T cellular therapy.
Karnofsky Index or Lansky Play-Performance Scale ≥ 60 % on pre-transplant evaluation. Karnofsky scores must be used for patients > 16 years of age and Lansky scores for patients < 16 years of age.
Able to give informed consent if > 18 years, or with a legal guardian capable of giving informed consent if < 18 years. Assent will be required for those capable of providing assent <18 years of age.
Adequate organ function (within 4 weeks of initiation of preparative regimen), defined as:
a) Pulmonary: FEV1, FVC, and corrected DLCO must all be ≥ 50% of predicted by pulmonary function tests (PFTs). For children who are unable to perform for PFTs due to age, the criteria are: no evidence of dyspnea at rest and no need for supplemental oxygen.
b) Renal: Creatinine clearance or radioisotope GFR 60 mL/min/1.73 m2 or a serum creatinine based on age/gender as follows (See protocol)
c) Cardiac: Shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA) or ejection fraction of ≥ 50% by echocardiogram or radionuclide scan (MUGA), choice of test according to local standard of care.
d) Hepatic: SGOT (AST) or SGPT (ALT) < 5 x upper limit of normal (ULN) for age. Conjugated bilirubin < 2.5 mg/dL, unless attributable to Gilbert’s Syndrome.
Exclusion Criteria
CR2: exclude patients with history of CNS relapse (i.e. in CR2 with history of CNS isolated or combined relapse; CNS 2 will also be considered as CNS 3 for this purpose) from the treatment arm of study (can be enrolled on the observational arm).
Patients who have received inotuzumab treatment prior to allogeneic HCT are NOT eligible for the study treatment arm. Inotuzumab treatment may increase the risk of VOD/SOS for any allogeneic HCT recipient, but could potentiate the risk for with busulfan-based myeloablation (study-directed non-TBI conditioning). All inotuzumab-treated patients are eligible for the observational arm (HCT center standard of care).
Patients receiving non-myeloablative conditioning are not allowed on the observational arm (reduced toxicity conditioning with Flu/Mel/Thio is allowed on the observational arm).
Pregnant or lactating females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants.
Patients with HIV or uncontrolled fungal, bacterial or viral infections are excluded. Patients with history of fungal disease during induction therapy may proceed if they have a significant response to antifungal therapy with no evidence or minimal evidence of non-progressive disease remaining by CT evaluation.
Patients with active CNS leukemia or any other active site of extramedullary disease at the time of enrollment are not permitted.
T-ALL and MPAL patients are only allowed on the observational arm.
Patients with genetic disorders (generally marrow failure syndromes) prone to secondary AML/ALL with known poor outcome are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis Congenita, etc).
