The main purpose of this study is to learn if a new combination of chemotherapy, in combination with low-dose radiation, will be safe for the patient, and at the same time provide the best opportunity to cure the bone marrow cancer. The combination of chemotherapy and radiation described in the study is considered 'low intensity.' Although the chemotherapy agents used in this study and for transplant are FDA approved, the chemotherapy treatment and conditioning regimens or combinations listed in this consent are not yet FDA approved.

The CliniMACS device is FDA approved for one type of T cell depletion (positive selection of the stem cells) but not approved yet for other type of T cell depletion, which is being studied on this protocol. This pilot study, along with other studies will serve as the basis for FDA approval, if outcomes are favorable.

Inclusion Criteria:

• Patients with one of the high risk myeloid diseases as outlined below. Patients must have ≤ 5% blasts on the last BM evaluation prior to starting the conditioning regimen. Diseases included on this protocol include:

  1. Acute Myeloid Leukemia (AML) in CR1 with intermediate or high risk features as defined below:

     °Cytogenetic abnormalities which are not considered "good risk" cytogenetic features (i.e t(8:21), t(15:17), inv 16 without c-kit mutations.

     And/or

     • Therapy related AML with history of antineoplastic therapy (radiation and/or chemotherapy) And/or
     • Normal karyotype with mutations of FLT3, RUNX1, TP53 mutation, ASXL1 or any others that are considered to be high risk

  2. AML in ≥ 2nd remission

  3. Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN overlap syndrome with:

     °International prognostic scoring system risk score INT-2 or high risk at the time of transplant evaluation.

     And/or

     • Any risk category if life-threatening cytopenia exists And/or
     • Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype.

  4. Chronic myelomonocytic leukemia (CMML)

  5. Chronic myeloid leukemia (CML) with the following features:

     °Patients who have failed or are intolerant to BCR-ABL tyrosine kinase inhibitors.

     And/or

     °CML with BCR-ABL mutation consistent with poor response to tyrosine kinase inhibition (e.g T351l mutation)

  6. Patients with severe aplastic anemia

• Chronic lymphocytic leukemia (CLL) with high risk disease as defined by the EBMT consensus criteria.

• Non-Hodgkin lymphoma meeting both of the following criteria:

  • Responding to therapy prior to enrollment.
  • Relapse after prior autologous bone marrow transplant or are ineligible for autologous bone marrow transplant.

• Multiple Myeloma with disease in the following categories:

  • Patients with relapsed multiple myeloma following autologous stem cell transplantation who have achieved at least partial response following additional chemotherapy
  • Patients with high risk cytogenetics at diagnosis must have achieved at least a partial response following autologous stem cell transplantation. Patients must have complex karyotype, del17p, t4;14, and/or t14;16 by FISH and/or del13 by karyotyping.

• Each patient must be willing to participate as a research participant and must sign an informed consent form.

• Organ Function and Performance Status Criteria:

  1. Patients be ≥ 18 years old.

  2. Patients must have a Karnofsky (adult) or Performance Status ≥ 70%.

  3. Patients must have adequate organ function measured by:

     • Cardiac: asymptomatic or if symptomatic, then LVEF at rest must be ≥ 40% and must improve with exercise.
     • Hepatic: < 5x ULN ALT and < 2x ULN total serum bilirubin, unless there is congenital benign hyperbilirubinemia.
     • Renal: CrCl >30ml/min (measured or calculated/estimated).
     • Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for hemoglobin)

Exclusion Criteria:

• Prior allogenic hematopoietic stem cell transplantation
• Prior radiation therapy with 400cGY or more of TBI
• BM with increased fibrosis (Reticulin stain > 1/3)
• Active and uncontrolled infection at time of transplantation
• HIV infection
• Seropositivity for HTLV-1
• Inadequate performance status/ organ function
• Pregnancy or breast feeding
• Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and research tests.

Donor Inclusion and Exclusion Criteria:

• Must be a 10/10 HLA genotypically match related or unrelated donor at all A, B, C, DRB1, and DQB1 loci, as tested by DNA analysis
• Able to provide informed consent for the donation process per institutional standards
• Meet standard criteria for donor collection as defined by the National Marrow Donor Program Guidelines