Nonmyeloablative Hematopoietic Cell Transplantation (HCT) for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors: A Pilot Trial of Peripheral Blood Stem Cells (PBSC) as the Donor Source

This is a pilot study to assess the safety and potential efficacy of haploidentical peripheral blood stem cell transplantation using a nonmyeloablative preparative regimen and post-transplant cyclophosphamide. The overall objective of this study is to collect the efficacy and safety data to provide the basis to decide whether a larger study of clinical efficacy is warranted in this setting.

Inclusion criteria

Subject

• Age< 70.
• Molecular based HLA typing will be performed for the HLA-A, -B, -Cw, DRB1 and -DQB1 loci to the resolution adequate to establish haplo identity. A minimum match of 5/10 is required. An unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral or low-likelihood of finding a matched, unrelated donor.
• Subjects must meet one of the disease classifications listed below:

Acute leukemias (includes T lymphoblastic lymphoma). Remission is defined as < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing ANC >1000/ul, including patients in CRp.

Acute Lymphoblastic Leukemia in high risk CR1 as defined by at least one of the following:

Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements White blood cell counts >30,000/mcL Patients over 30 years of age Time to complete remission >4 weeks Presence of extramedullary disease

Acute Myelogeneous Leukemia in high risk CR1 as defined by at least one of the following:

Greater than 1 cycle of induction therapy required to achieve remission Preceding myelodysplastic syndrome (MDS) Presence of Flt3 abnormalities FAB M6 or M7 leukemia or

Adverse cytogenetics for overall survival such as:

those associated with MDS Complex karyotype (≥ 3 abnormalities) Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], t(11;19)(q23;p13.1)

Acute Leukemias in 2nd or subsequent remission

Biphenotypic/Undifferentiated Leukemias in 1st or subsequent CR.

High-risk MDS status-post cytotoxic chemotherapy

Myelofibrosis

Burkitt's lymphoma: second or subsequent CR.

Lymphoma.

Chemotherapy-sensitive (complete or partial response; see response criteria Appendix C) large cell, Mantle Cell or Hodgkin's lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are ineligible for an autologous transplant or relapsed/progressed after autologous stem cell transplant.

Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan) and are ineligible for an autologous transplant or relapsed/progressed after autologous stem cell transplant..

• Patients with adequate physical function as measured by:

Cardiac: left ventricular ejection fraction at rest must be ≥ 35%.

Hepatic: bilirubin ≤ 2.5 mg/dL; and ALT, AST, and Alkaline Phosphatase < 5 x ULN.

Renal: serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function(creatinine clearance or GFR) > 40 mL/min/1.73m2.

Pulmonary: FEV1, FVC, DLCO (diffusion capacity) ≥ 40% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% on room air.

Performance status: Karnofsky/Lansky score ≥ 60%.

• Patients who have received a prior allogeneic HSCT and who have either rejected their grafts or who have become tolerant of their grafts with no active GVHD requiring immunosuppressive therapy.

Donor

• Donors must be HLA-haploidentical first-degree or second degree relatives of the patient.
• Age ≥ 18 years
• Weight ≥ 40 kg

Exclusion criteria

Subject

• HLA-matched donor able to donate.
• Pregnancy or breast-feeding.
• Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).

Donor

• Positive anti-donor HLA antibody.