Standard-of-Care Reduced-Intensity Conditioning with Total Body Irradiation for the Treatment of Acute Leukemia Undergoing First Allogeneic Blood or Marrow Transplantation

Status: active

This phase II trial compares the effect of standard-of-care (SOC) reduced-intensity conditioning (RIC) with lower-dose or higher-dose total body irradiation (TBI) for the treatment of acute leukemia undergoing first allogeneic blood or marrow transplantation (BMT). SOC RIC uses standard chemotherapy along with radiation before infusion of the cells from the transplant donor. A donor may be a relative or someone unrelated. Chemotherapy drugs, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink cancer. The radiation used prior to transplant, TBI, irradiates the entire body. Giving chemotherapy and TBI before a donor transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. This trial is being done to find out the optimal dose of TBI prior to allogeneic BMT. Using SOC RIC and the optimal dose of TBI may be safer, more tolerable and/or more effective in treating patients with acute leukemia undergoing first allogeneic BMT.

Inclusion Criteria

Age ≥ 0 years
Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia or lymphoma (ALL), or acute leukemia of mixed or ambiguous lineage per the 2022 World Health Organization classifications, with < 5% blasts on bone marrow morphologic analysis performed within 30 days of planned conditioning initiation * AML is generally defined as ≥ 20% myeloid blasts identified in the peripheral blood and/or bone marrow. Myeloid sarcoma is also recognized as an AML-defining entity. Situations in which AML can be diagnosed without a specific blast threshold met nor myeloid sarcoma present are when fusions involving RUNX1::RUNX1T1, CBFB::MYH11, DEK:NUP214, or RBM15::MRTFA are present; rearrangements involving KMT2A, MECOM, or NUP98 exist; or there is a mutation in NPM1 * B- or T-ALL is defined as the presence of lymphoid blasts identified in the peripheral blood and/or bone marrow with no specific blast threshold needed (acute lymphoblastic leukemia) or the presence of a lymphatic-based collection of lymphoblasts (acute lymphoblastic lymphoma) * Acute leukemia of mixed or ambiguous lineage is defined as mixed or ambiguous lineage blasts identified in the peripheral blood and/or bone marrow or the presence of a lymphatic-based collection (lymphoma) of mixed or ambiguous lineage blasts. A specific blast threshold does not need to be met * Patients with a documented diagnosis of myeloproliferative neoplasm (MPN), myelodysplastic syndrome or neoplasm (MDS), and/or MDS/MPN-overlap prior to diagnosis of acute leukemia may be included for randomization in this clinical trial so long as the patient has received at least 4 cycles of deoxyribonucleic acid (DNA) methyltransferase inhibitor (e.g., azacitidine, decitabine, decitabine/cedazuradine [Inqovi], and/or any other agent that works via this mechanism) or at least one cycle of induction chemotherapy. A list of antecedent diagnoses per the World Health Organization 2022 classification of hematolymphoid tumors that pertain to this inclusion criterion are listed below: ** MPN includes myelofibrosis, essential thrombocythemia, polycythemia vera, chronic neutrophilic leukemia, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, chronic myeloid leukemia (CML), or myeloproliferative neoplasm, not otherwise specified ** Myelodysplastic syndrome or neoplasm (MDS) ** MDS/MPN-overlap includes chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative neoplasm with neutrophilia, myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis, or myelodysplastic/myeloproliferative neoplasm, not otherwise specified ** Of note, patients without a documented history of one of these conditions prior to diagnosis of acute myeloid leukemia with myelodysplastic features would not be restricted to this specific criterion for study inclusion
No active extramedullary leukemia or known active central nervous system (CNS) involvement by malignancy. Such disease treated into remission is permitted
Patients must have a related or unrelated bone marrow or peripheral blood donor * Human leukocyte antigen (HLA)-matched (10/10) sibling donor (MSD) * HLA-matched (10/10) unrelated donor (MUD) * HLA-haploidentical (5/10) related donor (Haplo) * HLA-mismatched (6-9/10) unrelated donor (mMUD)
Planned allogeneic BMT using post-transplantation cyclophosphamide (PTCy) as a component of GVHD prophylaxis
Left ventricular ejection fraction >= 35% or shortening fraction > 25%
Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert’s syndrome or hemolysis)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x upper limit of normal (ULN)
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) >= 40% of predicted
Patients may enroll in other transplant-related trials (e.g., those testing post-transplant maintenance strategies or peri-transplant strategies for the management of donor specific antibodies) as long as other eligibility criteria are met and the requirements do not conflict with the treatment plan as outlined herein. Patients may also receive standard of care post-transplant maintenance therapies

Exclusion Criteria

Acute leukemia with PML::RARA fusion
Prior allogeneic BMT
Eastern Cooperative Oncology Group (ECOG) performance status > 2 or Karnofsky/Lansky score < 60
Patients with an additional active malignancy with a life expectancy < 2 years due to that disease
Symptomatic coronary artery disease
Uncontrolled infection
Patients who are pregnant or breastfeeding

PRIMARY OBJECTIVE:

I. Compare graft-versus-host disease-free, relapse-free survival (GRFS) between patients in the two cohorts.

SECONDARY OBJECTIVES:

I. Compare overall survival (OS) between patients in the two cohorts.

II. Compare relapse-free survival (RFS) between patients in the two cohorts.

III. Compare relapse incidence (RI) between patients in the two cohorts.

IV. Compare non-relapse mortality (NRM) between patients in the two cohorts.

V. Compare the incidence of both acute and chronic graft-versus-host disease (GVHD) between patients in the two cohorts.

VI. Compare the incidence of graft failure between patients in the two cohorts.

EXPLORATORY OBJECTIVES:

I. Compare rates of grade ≥ 3 toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria.

II. Compare rates of grade ≥ 2 noninfective cystitis according to CTCAE criteria.

III. Compare maximal grade of fatigue according to CTCAE criteria.

IV. Compare rates in the development of new malignancies between patients in the two cohorts.

V. Compare time to absolute neutrophil count (ANC) ≥ 1000/mm^3 and transfusion independence between patients in the two cohorts.

VI. Compare days of inpatient hospitalization from day -6 to day +56 between patients in the two cohorts.

VII. Compare the degree of T cell and total donor chimerism at different time points between groups.

VIII. Compare the level of markers of primary hypogonadism in women of menstruating age and men.

IX. Compare rates of intact fertility potential in women of menstruating age and men.

X. Compare patient-reported health outcomes in eight domains.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I:

SOC RIC: Patients receive chemotherapy per institutional SOC on study and undergo lower-dose TBI once on either day -3, -2 or -1.

ALLOGENEIC BMT: Patients receive an allogeneic BMT with T-cell replete peripheral blood stem cells or unmanipulated bone marrow per institutional practice intravenously (IV) once on day 0.

ARM II:

SOC RIC: Patients receive chemotherapy per institutional SOC on study and undergo higher-dose TBI once on either day -3, -2 or -1.

ALLOGENEIC BMT: Patients receive an allogeneic BMT with T-cell replete peripheral blood stem cells or unmanipulated bone marrow per institutional practice IV once on day 0.

Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and computed tomography (CT) scan during screening. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection throughout the trial. Patients may undergo biopsy during follow up.

After completion of study treatment, patients are followed up at days 28, 56, 90 and 180 and at year 1 and 2.

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Standard-of-Care Reduced-Intensity Conditioning with Total Body Irradiation for the Treatment of Acute Leukemia Undergoing First Allogeneic Blood or Marrow Transplantation

Inclusion Criteria

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United States

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Standard-of-Care Reduced-Intensity Conditioning with Total Body Irradiation for the Treatment of Acute Leukemia Undergoing First Allogeneic Blood or Marrow Transplantation

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