Double Cord Versus Haploidentical (BMT CTN 1101)

Reduced intensity conditioning (RIC) blood or marrow transplantation (BMT) has allowed older
and less clinically fit patients to receive potentially curative treatment with allogeneic
HCT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched
sibling may receive a graft from a suitably HLA-matched unrelated donor. However, up to a
third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated
donor (i.e., no more than a mismatch at a single locus). Even when a suitably matched
unrelated donor is identified, data from the National Marrow Donor Program (NMDP) indicate
that a median of four months is required to complete searches that result in transplantation;
thus, some number of patients succumb to their disease while awaiting identification and
evaluation of a suitably matched adult unrelated donor.

Single or dual center studies have shown that partially HLA-mismatched related bone marrow
(haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor
cells for RIC HCT, thus extending this treatment modality to patients who lack other donors.
In order to study the reproducibility, and thus, the wider applicability of these two
alternative donor strategies, The Blood and Marrow Transplantation Clinical Trials Network
(BMT CTN) conducted two parallel multicenter prospective Phase II clinical trials. These two
studies evaluated the safety and efficacy of related haplo-BM (BMT CTN 0603) and dUCB (BMT
CTN 0604) transplantation after RIC. Both of these alternative donor approaches produced
early results similar to that reported with unrelated donor, and even HLA-matched sibling,
HCT. These data demonstrate not only the efficacy of both of these approaches, but also that
both can be safely exported from the single center setting. Both haplo-BM and dUCB grafts can
be obtained rapidly for greater than 90% of patients lacking an HLA-matched donor. This study
will test the hypothesis that progression free survival at two years after RIC haplo-BM
transplantation is similar to the progression free survival after RIC dUCB transplantation.

Inclusion Criteria:

- Patients 18 to 70 years old

- Patients must have available both: a)One or more potential related mismatched donors
(biologic parent(s) or siblings (full or half) or children). At least low resolution
DNA based human leukocyte antigen (HLA) typing at HLA-A, -B, and -DRB1 for potential
haploidentical sibling donors is required. b)At least two potential umbilical cord
blood units identified. Each unit must have a minimum of 1.5 x 10^7/kg
pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units,
the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least
2.0 x 10^7/kg. Units must be HLA matched at a minimum of 4/6 to the recipient at
HLA-A, HLA-B (at low resolution using DNA based typing) and HLA-DRB1 (at high
resolution using DNA based typing). Confirmatory typing is not required for
randomization.

- Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) that is NOT
considered favorable-risk as defined by the presence of at least one of the following:
Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other Mixed Lineage Leukemia
(MLL) rearrangements; White blood cell counts of greater than 30,000/mcL (B-ALL) or
greater than 100,000/mcL (T-ALL)at diagnosis; Recipient age older than 30 years at
diagnosis; Time to CR greater than 4 weeks

- Acute Myelogeneous Leukemia (AML) in CR1 that is NOT considered as favorable-risk.
Favorable risk is defined as having one of the following: t(8.21) without CKIT
mutation, inv(16) without CKIT mutation or t(16;16), normal karyotype with mutated
NPM1 and not FLT-ITD, normal karyotype with double mutated CEBPA, Acute promyelocytic
leukemia (APL) in first molecular remission at end of consolidation

- Acute Leukemias in 2nd or subsequent CR

- Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR,
adult T-cell leukemia/lymphoma in first or subsequent CR

- Burkitt's lymphoma: second or subsequent CR

- Lymphoma fulfilling the following criteria: Chemotherapy-sensitive (at least stable
disease lymphomas that have failed at least 1 prior regimen of multi-agent
chemotherapy and are INELIGIBLE for an autologous transplant. Patients with chronic
lymphocytic leukemia (CLL) are not eligible regardless of disease status.

- Performance status: Karnofsky score greater than or equal to 70%.

Additional Patient Inclusion Criteria for Conditioning:

- Patients with Adequate Physical Function as Measured by: a. Cardiac: Left ventricular
ejection fraction at rest must be greater than or equal to 40%, or shortening fraction
less than 25%; b. Hepatic: Bilirubin less than or equal to 2.5 mg/dL, except for
patients with Gilbert's syndrome or hemolysis. Alanine aminotransferase (ALT),
aspartate aminotransferase (AST), and Alkaline Phosphatase less than 5 x upper limit
of normal; c. Renal: Serum creatinine within normal range, or if serum creatinine
outside normal range, then renal function (measured or estimated creatinine clearance
or GFR)greater than 40 mL/min/1.73m^; d. Pulmonary: Diffusing capacity of the lung for
carbon monoxide (DLCO) (corrected for hemoglobin), forced expiratory volume in one
second (FEV1), and forced vital capacity (FVC) greater than 50% predicted;

- Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm:
Patients must be HLA typed at high resolution using DNA based typing at the following
HLA-loci: HLA-A, -B, -C and DRB1 and have available a related haploidentical BM donor
with 2, 3, or 4 HLA-mismatches. A unidirectional mismatch in either the graft versus
host or host versus graft direction is considered a mismatch. The donor and recipient
must be HLA identical for at least one antigen (using high resolution DNA based
typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment
of this criterion shall be considered sufficient evidence that the donor and recipient
share one HLA haplotype, and typing of additional family members is not required.

- Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord
Blood Arm:

1. Patients must have available two UCB units fulfilling the following criteria:

1. Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total
nucleated cell dose. For non-red blood cell depleted units, the minimum
pre-cryopreserved total nucleated cell dose of each unit must be at least
2.0 x10^7/kg.

2. Units must be HLA matched at a minimum of 4/6 to the recipient at HLA -A,
HLA-B (at low resolution using DNA based typing), and HLA -DRB1 (at high
resolution using DNA based typing).

3. Additional graft selection criteria specified in section 2.5

2. Patients must have received at least one cycle of the cytotoxic chemotherapy
regimens (or regimen of similar intensity) listed in Appendix D within 3 months
of enrollment (measured from the start date of chemotherapy) OR have had an
autologous transplant within 24 months of enrollment OR receive 300 cGy as part
of the preparative regimen

Exclusion Criteria:

- Patients with suitably matched related or unrelated donor, as defined per
institutional practice.

- Recipients of prior autologous hematopoietic stem cell transplantation are ineligible
if disease recurrence occurred less than 6 months from their autologous stem cell
transplant.

- Current uncontrolled bacterial, viral or fungal infection (currently taking medication
with evidence of progression of clinical symptoms or radiologic findings).

- Prior allogeneic HCT.

- Patients with history of primary idiopathic myelofibrosis or any severe marrow
fibrosis.

- Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.

- Anti-donor HLA antibodies.

Additional exclusion criteria:

- Pregnancy or breast-feeding.

- Evidence of HIV infection or known HIV positive serology.