Eliminating Total Body Irradiation before a Donor Stem Cell Transplant in Treating Younger Patients with NGS-MRD Negative B-Acute Lymphoblastic Leukemia, the EndRAD Trial
This phase II trial studies how well eliminating total body irradiation (TBI) before a donor stem cell transplant works in treating younger patients with next-generation sequencing (NGS) minimal residual disease (MRD) negative B-acute lymphoblastic leukemia. TBI is normally used with chemotherapy in a conditioning regimen before a donor stem cell transplant and is considered related to improved outcomes. However, TBI has negative impacts on long-term growth and cognitive function of children and young adults. This study evaluates whether or not patients with NGS-MRD negative B-acute lymphoblastic leukemia have the same or similar medical outcome if they do not receive TBI before a donor stem cell transplant.
- < 5% blasts by morphology pre-HCT
- No evidence of central nervous system (CNS) disease (CNS2 not allowed) or other extramedullary disease before enrollment on treatment and observational arms of the study
- OBSERVATIONAL ARM (HCT STANDARD OF CARE):
- Any patient with ALL who undergoes myeloablative HCT * Reduced toxicity conditioning with fludarabine (Flu)/melphalan (Mel)/thiotepa (Thio) is acceptable on the observational arm
- Patients who are pre-HCT NGS-MRD positive * Patients < 3 years old with pre-HCT NGS-MRD positive, consider busulfan (Bu)/Flu/Thio non-TBI conditioning regimen, but it is at the discretion of the treating center as to which conditioning regiment to use (study non-TBI conditioning regimen is not mandated) ** Centers may avoid using TBI-based conditioning for children <3 years old (regardless of the MRD status) as institutional standard practice
- Patients < 1 year old who are pre-HCT NGS-MRD negative * Consider Bu/Flu/Thio non-TBI conditioning regimen, but it is at the discretion of the treating center as to which conditioning regimen to use (study non-TBI conditioning regimen is not mandated
- Patients who are pre-HCT NGS-MRD negative (first complete remission [CR1]/second complete remission [CR2]) who received inotuzumab ozogamicin therapy before proceeding to HCT
- Patients who are pre-HCT NGS-MRD negative and will be receiving haploidentical HCT
- Patients who are pre-HCT NGS-MRD negative in CR2 with history of CNS relapse
- Patients who have received blinatumomab, but are > CR2 prior to HCT
- Patients who have received chimeric antigen receptor (CAR)-T cellular therapy, but are > CR2 prior to HCT
- Patients with pre-HCT NGS-MRD negative in >= third complete remission (CR3)
- Any T-ALL and MPAL patients undergoing first allogeneic HCT
- Any patient who is pre-HCT NGS-MRD negative and eligible for participation in the treatment arm but family does not consent for treatment arm or treating physician believe it is in the patient best interest not to enroll on the treatment arm
- Centers may avoid using TBI-based conditioning for children < 3 years old (regardless of the MRD status) as institutional standard practice. For patients < 3 years old on the observational arm, centers may consider using the study Bu/Flu/Thio non-TBI conditioning regimen, but it is at the discretion of the treating center as to which conditioning regimen to use (study non-TBI conditioning regimen is not mandated)
- TREATMENT ARM (PHASE II):
- Pre-HCT NGS-MRD negative
- Disease status: * 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 deoxyribonucleic acid [DNA] index < 0.81) ** Persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction (e.g. Philadelphia chromosome [Ph] positive [+], 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 * CR2 indications: B-ALL in second remission (< 5% blasts by morphology pretransplant) 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
- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and corrected diffusion capacity of the lung for carbon monoxide (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 (within 4 weeks of initiation of preparative regimen)
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 4 weeks of initiation of preparative regimen): * Age 1 to < 2 years: 0.6 (male), 0.6 (female) * Age 2 to < 6 years: 0.8 (male), 0.8 (female) * Age 6 to < 10 years: 1 (male), 1 (female) * Age 10 to < 13 years: 1.2 (male), 1.2 (female) * Age 13 to < 16 years: 1.5 (male), 1.4 (female) * Age >= 16 years: 1.7 (male), 1.4 (female) * The threshold creatinine values in this table are from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control (CDC)
- 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 (within 4 weeks of initiation of preparative regimen)
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x upper limit of normal (ULN) for age (within 4 weeks of initiation of preparative regimen)
- Conjugated bilirubin < 2.5 mg/dL, unless attributable to Gilbert’s Syndrome (within 4 weeks of initiation of preparative regimen)
- DONOR/STEM CELL SOURCE SELECTION ON STUDY TREATMENT ARM:
- Human leukocyte antigen (HLA)-identically matched siblings
- If no HLA-identically matched sibling is available, then the following stem cell sources are acceptable on the study treatment arm: * Unrelated or other related donors must be matched at 10/10 or 9/10 alleles (HLA-A, B, C, DRB1, and DQB1 at high resolution). Additional matching for DPB1 will be left to the discretion of the treating center * Unrelated cord blood units must be matched at 4/6, 5/6, or 6/6 antigens (HLA-A, B, [low/intermediate] and DRB1 [high resolution]). Published data (58-59) show lower non-relapse mortality (NRM) when patients receive allele-level matched units at 8/8, 7/8, or 6/8 (HLA-A, B, C, and DRB1 at high resolution). Allele-level typing and matching of all cord blood transplants on this study is encouraged. Use of lower allele level matching of cords may lead to higher treatment related mortality (TRM) and are discouraged on this study, but can be used if there are no other options available. The minimum pre-thaw cell dose of 3 x 10^7 total nucleated cells (TNC)/kg of recipient weight is required. Two cords can be used if needed to achieve the recommended pre-thaw cell dose. The two units must each match the recipient at 4/6 antigens and must match each other at a minimum of 3/6 antigens. As with single cord blood transplants, allele level matching of double cord blood units to minimize risk for non-relapse mortality (NRM) and transplant-related mortality (TRM) is advised but not mandated by the study * Note: Centers using unlicensed cord blood must consent the patient on the National Marrow Donor Program (NMDP) cord blood investigational new drug (IND) protocol or other cord blood IND protocols as appropriate in order to use such units on this study
- Bone marrow (BM) is the preferred stem cell source for all allogeneic related and unrelated donors. Peripheral blood stem cells (PBSC) is allowed only if the donor is unable or unwilling to give bone marrow * Note: Cell dose for BM or PBSC will be according to local institutional standard
- ALTERNATIVE DONORS FOR OBSERVATIONAL ARM
- Haploidentical, other cord or other mismatched related donor (< 9/10 HLA-match) HCT will be permitted on the observational arm
- 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 veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (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 human immunodeficiency virus (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 computed tomography (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 acute myeloid leukemia (AML)/ALL with known poor outcome are not eligible (Fanconi anemia, Kostmann syndrome, dyskeratosis congenita, etc)
Locations & Contacts
Contact: Anna Beata Pawlowska
Contact: Hisham Abdel-Azim
Contact: Amy Kathleen Keating
Contact: Jodi Lynn Skiles
Contact: Kris Michael Mahadeo
U.S. Minor Outlying Islands
Contact: Troy C Quigg
Trial Objectives and Outline
I. Estimate the 2-year event free survival (EFS) and the 2-year cumulative incidences of relapse and non-relapse mortality in pre-hematopoietic cell transplantation (HCT) NGS-MRD negative patients with B-acute lymphoblastic leukemia (ALL) undergoing a non-TBI based conditioning regimen.
I. Estimate overall survival (OS) following a non-TBI based conditioning regimen in B-ALL patients who are pre-HCT NGS-MRD negative.
II. Correlate the presence of and level of pre-HCT NGS-MRD in bone marrow (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.
III. 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).
IV. 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.
V. 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.
VI. Assess the effect of acute and chronic graft versus host disease (GVHD) on relapse, EFS, and OS in B-ALL patients with and without the presence of MRD measured by NGS or by MFC.
VII. Screen B-ALL clones at relapse post-HCT to assess whether changes in B-cell clonal rearrangements occur compared to pre-HCT blasts.
VIII. 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.
IX. 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).
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I (NON-TBI TREATMENT): NGS-MRD negative patients receive fludarabine phosphate intravenously (IV) every (q) 24 hours on days -7 to -3, busulfan IV once daily (QD) or q 6 hours on days -7 to -4, and thiotepa IV q 12 hours on day -2. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0.
ARM II (OBSERVATIONAL): NGS-MRD positive patients receive conditioning regimen at the discretion and practice of the local institution. Patients also undergo allogeneic HSCT on day 0.
After completion of study treatment, patients are followed up at 42, 100, 180, 270, and 365 days, then yearly for up to 5 years.
Trial Phase & Type
Children's Hospital Los Angeles
Secondary IDs NCI-2019-02525
Clinicaltrials.gov ID NCT03509961