Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies

Patient Inclusion Criteria:

1. Patient age 0.5-75 years

2. Absence of a suitable related or unrelated bone marrow donor who is molecularly
matched at HLA-A, B, Cw, DRB1, and DQB1.

3. Absence of a suitable partially HLA-mismatched (haploidentical), first-degree
related donor. Donors who are homozygous for the CCR5delta32 polymorphism are given
preference.

4. Eligible diagnoses:

1. Relapsed or refractory acute leukemia in second or subsequent remission, with
remission defined as <5% bone marrow blasts morphologically

2. Poor-risk acute leukemia in first remission, with remission defined as <5% bone
marrow blasts morphologically:

- AML with at least one of the following:

- AML arising from MDS or a myeloproliferative disorder, or secondary
AML

- Presence of Flt3 internal tandem duplications

- Poor-risk cytogenetics: Complex karyotype [> 3 abnormalities],
inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of
t(9;11), or abnormalities of chromosome 5 or 7

- Primary refractory disease

- ALL (leukemia and/or lymphoma) with at least one of the following:

- Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL
rearrangement

- Clear evidence of hypodiploidy

- Primary refractory disease

- Biphenotypic leukemia

3. MDS with at least one of the following poor-risk features:

- Poor-risk cytogenetics (7/7q minus or complex cytogenetics)

- IPSS score of INT-2 or greater

- Treatment-related MDS

- MDS diagnosed before age 21 years

- Progression on or lack of response to standard DNA-methyltransferase
inhibitor therapy

- Life-threatening cytopenias, including those generally requiring greater
than weekly transfusions

4. Interferon- or imatinib-refractory CML in first chronic phase, or non-blast
crisis CML beyond first chronic phase.

5. Philadelphia chromosome negative myeloproliferative disease.

6. Chronic myelomonocytic leukemia.

7. Juvenile myelomonocytic leukemia.

8. Low-grade non-Hodgkin lymphoma (including SLL and CLL) or plasma cell neoplasm
that has:

- progressed after at least two prior therapies (excluding single agent
rituximab and single agent steroids), or

- in the case of lymphoma undergone histologic conversion;

- patients with transformed lymphomas must have stable disease or better.

9. Poor-risk CLL or SLL as follows:

- 11q deletion disease that has progressed after a combination chemotherapy
regimen,

- 17p deletion disease,

- or histologic conversion;

- patients with transformed lymphomas must have stable disease or better.

10. Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or
better to last therapy:

- NK or NK-T cell lymphoma, hepatosplenic T-cell lymphoma, or subcutaneous
panniculitic T-cell lymphoma, blastic/ blastoid variant of mantle cell
lymphoma

- Hodgkin or aggressive non Hodgkin lymphoma that has failed at least one
multiagent regimen, and the patient is either ineligible for autologous
BMT or autologous BMT is not recommended.

- Eligible subtypes of aggressive non-Hodgkin lymphoma include:

- mantle cell lymphoma

- follicular grade 3 lymphoma

- diffuse large B-cell lymphoma or its subtypes, excluding primary CNS
lymphoma

- primary mediastinal large B-cell lymphoma

- large B-cell lymphoma, unspecified

- anaplastic large cell lymphoma, excluding skin-only disease

- Burkitt's lymphoma or atypical Burkitt's lymphoma (high-grade B-cell
lymphoma, unclassifiable, with features intermediate between diffuse
large B-cell lymphoma and Burkitt's), in complete remission

5. Patients with CLL, SLL, or prolymphocytic leukemia must have < 20% bone marrow
involvement by malignancy (to lower risk of graft rejection).

6. One of the following, in order to lower risk of graft rejection:

- Cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or
alemtuzumab within 3 months prior to start of conditioning; or

- Previous BMT within 6 months prior to start of conditioning.

NOTE: Patients who have received treatment outside of these windows may be eligible
if it is deemed sufficient to reduce graft rejection risk; this will be decided on a
case-by-case basis by the PI or co-PI.

7. Any previous BMT must have occurred at least 3 months prior to start of
conditioning.

8. Adequate end-organ function as measured by:

1. Left ventricular ejection fraction greater than or equal to 35%, or shortening
fraction > 25%, unless cleared by a cardiologist

2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT
and AST < 5 x ULN

3. FEV1 and FVC > 40% of predicted; or in pediatric patients, if unable to perform
pulmonary function tests due to young age, oxygen saturation >92% on room air

9. ECOG performance status < 2 or Karnofsky or Lansky score > 60

Patient Exclusion Criteria:

- Not pregnant or breast-feeding.

- No uncontrolled bacterial, viral, or fungal infection.

- Note: HIV-infected patients are potentially eligible. Eligibility of
HIV-infected patients will be determined on a case-by-case basis.

- No previous allogeneic BMT (syngeneic BMT permissible).

- Active extramedullary leukemia or known active CNS involvement by malignancy. Such
disease treated into remission is permitted.

Donor Inclusion Criteria:

1. Potential donors consist of:

- Unrelated donors

- Second-degree relatives

- First cousins

2. The donor and recipient must be identical at at least 5 HLA alleles based on high
resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele
matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched
for a class II gene (HLA-DRB1 or -DQB1).

3. Meets institutional selection criteria and medically fit to donate. 4 . Lack of
recipient anti-donor HLA antibody. Note: In some instances, low level, non-cytotoxic
HLA specific antibodies may be permissible if they are found to be at a level well
below that detectable by flow cytometry. This will be decided on a case-by-case
basis by the PI and one of the immunogenetics directors. Pheresis to reduce anti-HLA
antibodies is permissible; however eligibility to proceed with the transplant
regimen would be contingent upon the result.

Donor Exclusion Criteria:

- Donor must not be HLA identical to the recipient.

- Has not donated blood products to recipient.