ABBA CORD: dCBT w/ Abatacept for aGVHD Prophylaxis

The goal of this clinical trial is to see if adding abatacept to tacrolimus and MMF prevents or reduces the chances of acute graft versus host disease which is a complication that can occur after transplant in participants with blood cancer. The usual therapy for graft versus host disease prevention after a cord blood transplant includes tacrolimus and MMF. The main question this clinical trial aims to answer is whether or not abatacept will be safe and effective in reducing aGVHD rates in dCBT.

Participants will:

* Partake in exams, tests, and procedures as part of usual cancer care.
* Partake in conditioning, which is the treatment that is given before a transplant.
* Have a cord blood transplant.
* Partake in radiation following the transplant.

Cord blood (CB) is a valuable alternative graft source for patients with hematologic malignancies in need of allogeneic transplantation who lack human leukocyte antigen (HLA)-matched adult donors. In Black, Asian, Hispanic populations, the chance of finding a HLA matched donor is 23%, 41%, and 46%, respectively. CB allows for greater HLA difference between donor and recipient, and increases the availability of donors, and therefore transplant, to these populations. Retrospective analyses and prospective trials demonstrate that recipients of double CB transplant (dCBT) have a grade II-IV acute graft versus host disease (aGVHD) rate of 45-90% and grade III-IV aGVHD rates up to 24%. This high aGVHD rate is likely due to the HLA-disparities between donor and recipient, which also drives a robust graft versus leukemia response8. Anti-thymocyte globin has been used in dCBT to reduce the incidence of aGVHD, but is no longer recommended due to delayed immune-reconstitution of the CB grafts. The ABA2 trial demonstrated efficacy and safety of abatacept as prophylaxis for aGVHD in HLA-mismatched unrelated donors (MMUD), significantly reducing the rate both of grade III-IV aGVHD and grade II-IV aGVHD in 7/8 MMUD when compared to historical controls. Our hypothesis is that abatacept will be safe and effective in reducing aGVHD rates in dCBT.

Eligibility Criteria:
Inclusion Criteria:

* Patients with the following hematologic malignancies:

  * Acute myelogenous leukemia (AML): High-risk and intermediate-risk AML including:

    * Antecedent hematological disease (e.g., myelodysplasia (MDS))
    * Treatment-related leukemia
    * Complete Remission (CR1) with poor or intermediate-risk cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23, del 5, del 7, complex cytogenetics)
    * CR2 or CR3
    * Induction failure or 1st relapse with \< 10% blasts in the marrow
  * Acute lymphoblastic leukemia (ALL):

    * High-risk CR1 including:

      * Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23 rearrangements)
      * Philadelphia chromosome-like ALL
      * Presence of minimal disease by flow cytometry after 2 or more cycles of chemotherapy
    * No CR within 4 weeks of initial treatment
    * Induction failure with \< 10% blasts in the marrow
    * CR2 or CR3
  * Myelodysplastic syndromes (MDS), Intermediate, High or Very High Risk by the revised international prognostic scoring system or treatment related MDS.
  * Bi-phenotypic or mixed-phenotypic acute leukemia in:

    * CR.
    * Induction failure or 1st relapse with \< 10% blasts in the marrow.
  * Chronic Myelogenous Leukemia (CML) in second chronic phase after accelerated or blast crisis.
  * Chronic Myelomonocytic Leukemia (CMML)
  * Hodgkin's Lymphoma that is relapsed or refractory
* Age \> or equal to 18 years, \< or equal to 70yrs
* KPS \> or equal to 80 for Flu/Cy/Thio/TBI; KPS \> 60 for Flu/Treo/TBI
* Patients without a suitable HLA-matched related or unrelated donor
* Patient with the following CB units:

  * At least two 4-8/8 HLA high resolution matched CB units. Both must have a cell dose of 1.5x107 TNC/kg each and 1.5x105 CD34+/kg
  * A minimum of 1 CB unit as back up.
* Concurrent Therapy for Extramedullary Leukemia or CNS Lymphoma: Concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia, and CNS lymphoma including standard intrathecal chemotherapy and/or radiation therapy will be allowed as clinically indicated. Such treatment may continue until the planned course is completed. Subjects must be in CNS remission at the time of protocol enrollment if there is a history of CNS involvement. Maintenance therapy after transplant is allowed.
* Subjects must have the ability to understand and the willingness to sign a written informed consent document.
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of \< 1% per year during the treatment period and for 12 months after the last dose of abatacept.
* A woman is considered to be of childbearing potential if she is \< 60 years old, postmenarcheal, has not reached a postmenopausal state (\< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

  * Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures with female partners of reproductive potential, and agreement to refrain from donating sperm, as defined below:

  * With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for 12 months after the last dose of abatacept. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 12 months after the last dose of abatacept.
  * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

* Patients with inadequate Organ Function as defined by:

  * Creatinine clearance \< 50ml/min
  * Bilirubin \> 2X institutional upper limit of normal unless Gilbert syndrome
  * AST (SGOT) \> 3X institutional upper limit of normal
  * ALT (SGPT) \> 3X institutional upper limit of normal
  * Pulmonary function: DLCOc \< 60% normal
  * Cardiac: left ventricular ejection fraction \< 50
* Patients with uncontrolled inter-current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant or breastfeeding women are excluded from this study because chemotherapy involved with RIC have the significant potential for teratogenic or abortifacient effects.
* Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.
* Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.
* Presence of donor-specific antibodies against chosen graft source.
* Hematopoietic Cell Transplantation Comorbidity index (HCT-CI) \> 5.
* Prior autologous or allogenic stem cell transplant within the preceding 12 months.