Total Marrow and Lymphoid Irradiation Fludarabine and Melphalan Before Donor Stem Cell Transplant in Treating Participants With High-Risk Acute Leukemia or Myelodysplastic Syndrome

  • End date
    Dec 19, 2021
  • participants needed
  • sponsor
    City of Hope Medical Center
Updated on 19 February 2021
stem cell transplantation
myeloid leukemia
lymphoid leukemia
chromosomal abnormalities
acute leukemia
white blood cell count
carbon monoxide
ejection fraction
bone marrow procedure
lymphocytic leukemia
serum bilirubin
serum bilirubin level
white blood cells
blood cell count
chromosome abnormality


This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor stem cell transplant in treating participants with high-risk acute leukemia or myelodysplastic syndrome. Giving chemotherapy, such as fludarabine and melphalan, and total marrow and lymphoid irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.



I. To determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of total marrow and lymphoid irradiation (TMLI) with fixed doses of fludarabine and melphalan (FM100) as a preparative regimen in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT) and who are not eligible for standard myeloablative regimens, with either a matched donor (Arm A) or a haploidentical donor (Arm B).

II. To describe toxicities attributable to TMLI by dose level in patients treated under this regimen.


I. To evaluate the safety of the regimen, at each dose level, by assessing the following: type, frequency, severity, attribution, time course and duration of adverse events, including acute/chronic graft versus host disease (GVHD), infection and delayed engraftment.

II. To investigate the temporal effect of bone marrow residual damage in alloHCT patients after TMLI/FM100.

III. To estimate overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

IV. Assess minimal residual disease (MRD) from bone marrow aspirates on days 30, 100, and 180 post-transplant and describe its relation to TMLI dose level and patient disease status.

V. To evaluate effect of TMLI/FM100 conditioning on immune reconstitution after alloHCT in patients receiving stem cells from matched or haploidentical donors.

OUTLINE: This is a dose-escalation study of TMLI.

Participants undergo TMLI twice daily (BID) on days -8 to -5, and receive fludarabine intravenously (IV) on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.

After completion of study treatment, participants are followed up twice weekly for 100 days, twice monthly for 6 months, and then monthly or yearly for up to 2 years.

Condition Bone marrow disorder, childhood ALL, Minimal Residual Disease, Preleukemia, Acute myeloid leukemia, MYELODYSPLASTIC SYNDROME, Myelodysplastic Syndromes (MDS), Acute Myelogenous Leukemia (AML), Acute Myeloid Leukemia in Remission, Secondary Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia in Remission, Hematopoietic Cell Transplantation Recipient, Lymphocytic Leukemia, Acute, acute lymphoblastic leukemia, leukemia, acute lymphoblastic, myelodysplastic syndromes, myelodysplastic syndrome (mds), secondary aml, acute lymphoid leukaemia, acute lymphocytic leukemia, acute lymphoblastic leukemia (all), acute myelogenous leukemia, anll, acute myeloblastic leukemia
Treatment laboratory biomarker analysis, melphalan, Fludarabine, Total Marrow Irradiation
Clinical Study IdentifierNCT03494569
SponsorCity of Hope Medical Center
Last Modified on19 February 2021


Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 12 yrs?
Gender: Male or Female
Do you have any of these conditions: Secondary Acute Myeloid Leukemia or acute myeloblastic leukemia or childhood ALL or Lymphocytic Leukemia, Acute or myelodysplastic syndrome (mds) or M...?
Do you have any of these conditions: childhood ALL or Acute Myeloid Leukemia in Remission or Hematopoietic Cell Transplantation Recipient or acute lymphoblastic leukemia or leukemia, acut...?
Do you have any of these conditions: myelodysplastic syndrome (mds) or acute lymphoblastic leukemia or acute lymphoid leukaemia or Bone marrow disorder or Acute myeloid leukemia or childh...?
Eligible patients with a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories
Acute myelogenous leukemia
Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5, 5q-, -7, 7q-, 11q23-non t (9;11), inv (3), t (3;3),t (6;9), t (9;22) and complex karyotypes ( 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease
Patients with active disease
Patients with chemosensitive active disease
Acute lymphocytic leukemia
Patients with de novo or secondary disease according to NCCN guidelines for ALL hypoploidy (< 44 chromosomes); t (v;11q23): MLL rearranged; t (9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis ( 30,000 for B lineage or 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p
Patients with active disease
Patients with chemosensitive active disease
Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories
Patients 12 years and < 55 years are also included if they are not candidates for myeloablative conditioning regimens due to comorbidities
Karnofsky or Lansky performance status of 70
A pretreatment measured creatinine clearance (absolute value) of 60 ml/minute
Patients must have a serum bilirubin 2.0 mg/dl
Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) 2.5 times the institutional upper limits of normal
Ejection fraction measured by echocardiogram or multigated acquisition (MUGA) 50%
Carbon monoxide diffusing capacity (DLCO) and forced expiratory volume FEV1 > 50% predicted
Patients should have discontinued all previous intensive therapy, chemotherapy or radiotherapy for 2 weeks prior to commencing therapy on this study
NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs); FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
All patients with prior radiation treatment to the lung, liver, and kidney will be excluded; for other scenarios of prior radiation treatment, up to 2000 cGY at 2 gray Gy per day will be allowed; inclusion of patients with previous radiation exposure will be determined based on the radiation oncologist MD evaluation and judgment
DONOR: Arm A: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate primed blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched unrelated donor; DQ or DP mismatch is allowed per discretion of the principal investigator
DONOR: Arm B: The recipient must have a related donor genotypically HLA-A, B, C and DRB1 loci haploidentical to the recipient; no HLA matched sibling or matched unrelated donor is available; DSA is allowed with desensitization done if recommended by donor selection committee (DSC) per City of Hope (COH) standard operating procedures (SOP)
DONOR: Both arms: All donors in both arms should be evaluated and approved by DSC

Exclusion Criteria

Having any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
Receiving any investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning
NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs), FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the regimen
Patients with other malignancies are ineligible for this study, other than non-melanoma skin cancers
The recipient has another medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery in which the opinion of the principal investigator would place the recipient at unacceptable risk
Patients may not have had a prior autologous or allogeneic transplant
Patients may not have received more than 3 prior lines of intensive chemotherapy, where the regimen intent was to induce remission
In the opinion of the principal investigator (PI), the participant has a condition that will preclude them from complying with study treatment
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
All subjects must have the ability to understand and the willingness to sign a written informed consent; they are to give voluntary written informed consent before performance if any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; cognitively impaired subjects will be included only if their guardian or legal representative agrees to sign the written informed consent
DONOR: Donor selection for both arms must be approved by the donor selection committee
DONOR: Evidence of active infection
DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy or leukapheresis
DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy could be harvested for bone marrow (BM) if safer for the donor and if approved by the principal investigator (PI)
DONOR: Human immunodeficiency virus (HIV) positive
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