Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies

Patient Inclusion Criteria:

Patient age 0.5-75 years
Absence of a suitable related or unrelated bone marrow donor who is molecularly matched at HLA-A, B, Cw, DRB1, and DQB1.
Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor. Donors who are homozygous for the CCR5delta32 polymorphism are given preference.

Eligible diagnoses:

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

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

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
Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase.
Philadelphia chromosome negative myeloproliferative disease.
Chronic myelomonocytic leukemia.
Juvenile myelomonocytic leukemia.

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.

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.

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

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.

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

Adequate end-organ function as measured by:

Left ventricular ejection fraction greater than or equal to 35%, or shortening fraction > 25%, unless cleared by a cardiologist
Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST < 5 x ULN
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
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:

Potential donors consist of:

Unrelated donors
Second-degree relatives
First cousins
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).
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.