Optimized Cord Blood Transplantation for the Treatment of Patients With High-risk Hematologic Malignancies Who Have Relapsed After First Allogeneic Stem Cell Transplantation

Inclusion Criteria

1. Patient aged 0-60 y/o at the time of consent.

2. Patient must have relapsed >100 days since first transplant.

3. Diagnosis and Disease Status:

   a. Acute myelogenous leukemia (AML): i. Patients in morphologic remission at the time of transplant, with or without persistent cytogenetic, flow cytometric, or molecular aberrations, or those with hypocellular marrows at time of transplant, are eligible.

   b. Acute lymphoblastic leukemia (ALL): i. Patients with less than 5% blasts at time of transplant, with or without persistent cytogenetic, flow cytometric or molecular aberrations, or those or who have hypocellular bone marrows, are eligible.

   c. Other acute leukemias: i. Acute leukemias of ambiguous lineage or mixed phenotype with less than 5% blasts at time of transplant, with or without persistent cytogenetic, flow cytometric or molecular aberrations, or those who have hypocellular bone marrows, are eligible.

   d. Myelodysplastic Syndromes (MDS) or CMML without myelofibrosis. i. Includes MDS with any IPSS risk category.

4. Prior treatment:

   1. To be eligible for this study, patients need to have received one prior allogeneic stem cell transplantation.
   2. To prevent graft rejection, patients who received only non-lymphodepleting agents for their malignancy (hypomethylating agents, venetoclax, hydroxyurea, TKIs, etc.), or patients who received lymphodepleting chemotherapy > 3 months prior to scheduled admission, may additionally receive fludarabine 25 mg/m2 daily x 3 days for lymphodepletion 14-42 days (aiming for 2-4 weeks) prior to admission, at the investigator's discretion, in order to qualify for the protocol.

5. Karnofsky score equal or greater than 70% (See Appendix B; inpatient Leukemia service transfers without discharge are acceptable provided patient has equivalent KPS as if were outpatient).

6. Renal and Liver function:

   1. Calculated creatinine clearance > 50 ml/min.
   2. Bilirubin < 2 mg/dL (unless benign congenital hyperbilirubinemia or hemolysis).
   3. ALT < 5 x upper limit of normal (ULN).

7. Pulmonary function: Spirometry (FVC and FEV1) and corrected DLCO > 60% predicted.

8. Left ventricular ejection fraction (MOD-bp) > 50%.

9. Graft Criteria:

   1. Two CB units will be selected according to the current MDACC CB unit selection algorithm.
   2. High resolution 8-allele HLA typing and recipient HLA antibody profile will be performed.
   3. Unit selection will occur based on HLA-match, total nucleated cell (TNC), and CD34+ cell dose adjusted per patient body weight.
   4. The bank of origin will also be considered.
   5. Donor-specific HLA antibodies, if present, will also be taken into consideration.
   6. Each CB unit must be at least 3/8 HLA-matched to the patient considering high-resolution 8-allele HLA typing.
   7. Each CB unit will be required to have a cryopreserved TNC dose of at least 1.5 x 107 TNC/ recipient body weight (TNC/ kg).
   8. Each CB unit will be required to have a cryopreserved CD34+ cell dose of at least 1.5 x 105 CD34+ cells/ recipient body weight (CD34+ cells/kg).
   9. A minimum of one unit will be reserved as a backup graft.
   10. Each CB unit will be required to be cryopreserved in standard cryovolume. (24-27 ml/s per unit) and be red blood cell depleted.

Exclusion Criteria

1. Diagnosis of myelofibrosis or other malignancy with moderate-severe bone marrow fibrosis.

2. Two prior stem cell transplants of any kind.

3. Prior involved field radiation therapy that would preclude safe delivery of 400cGy TBI in the opinion of Radiation Oncology.

4. Active and uncontrolled infection at the time of transplantation.

5. Active and uncontrolled GVHD at the time of transplantation.

6. Pregnant or breastfeeding.

7. Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, long-term follow-up, and research tests.

8. The effects of chemotherapy on the developing human fetus are unknown. For this reason and because chemotherapy agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

   • Postmenopausal (no menses in greater than or equal to 12 consecutive months).

   • History of hysterectomy or bilateral salpingo-oophorectomy.

   • Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).

   • History of bilateral tubal ligation or another surgical sterilization procedure.

     • Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
     • Men treated or enrolled in this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of chemotherapy administration.

9. Ability to understand and the willingness to sign a written informed consent document.

10. Patients with psychiatric illness/social situations that would limit compliance with study requirements.