Fludarabine and Busulfan vs. Fludarabine, Busulfan and Total Body Irradiation

Inclusion Criteria:

* Diagnosis of acute myelogenous leukemia, chronic myelogenous leukemia, other myeloproliferative disorder, or myelodysplastic syndrome
* Any stage of disease will be considered for transplantation
* Have a suitable related or unrelated donor (Section 3.3)
* Age ≥18 but \<70 yrs
* KPS of ≥70%
* Recovery from all hematologic and non-hematology toxicities from previous therapies.

Exclusion Criteria:

* Diagnosis other than acute myelogenous leukemia, myeloproliferative disorder, or myelodysplastic syndrome
* Chemotherapy or radiotherapy within 14 days of initiating treatment in this study with the exception of lenalidomide, decitabine, azacitidine, imatinib mesylate, dasatinib, nilotinib hydrochloride and hydroxyurea
* Prior dose-intense therapy requiring HSC support within 56 days of initiating treatment in this study
* Uncontrolled bacterial, viral, fungal or parasitic infections
* Uncontrolled CNS metastases
* Known amyloid deposition in heart
* Organ dysfunction

  * LVEF \<40% or cardiac failure not responsive to therapy
  * FVC, FEV1, or DLCO \<50% of predicted and/or receiving supplementary continuous oxygen
  * Evidence of hepatic synthetic dysfunction, or total bilirubin \>2x or AST \>3x ULN
  * Measured creatinine clearance \<20 ml/min
  * Karnofsky score \<70%
* Life expectancy limited by another co-morbid illness
* Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
* Female subject is pregnant or breast-feeding (women) or unwilling to use acceptable birth control methods (men or women) for twelve months after treatment. Confirmation that the subject is not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
* Documented hypersensitivity to fludarabine or melphalan or to bortezomib, boron or mannitol or any components of the formulation
* Patients unable or unwilling to provide consent
* Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant
* Patient has received other investigational drugs with 14 days before enrollment
* Serious medical or psychiatric illness likely to interfere with participation in this clinical study

Donor Inclusion and Exclusion Criteria

Donor Inclusion Criteria:

HLA 6/6 (HLA-A, B, DrB1) related donor or 7/8 (HLA-A, B, C, DrB1) unrelated donor Related donors will be evaluated in accordance with HUMC standard practice guidelines for the evaluation and management of allogeneic donors Unrelated donors will be identified, evaluated, and managed in accordance with National Marrow Donor Program standards Age ≥18 and \<70 yrs KPS of ≥70% Willing to donate bone marrow using standard techniques or peripheral blood HSC by leukapheresis Have adequate veins for apheresis or agree to placement of a central venous catheter (femoral, subclavian) if donating peripheral blood HSC

Donor Exclusion Criteria Identical twin Female donors who are pregnant or breastfeeding Infection with HIV or viral hepatitis (B or C) Known allergy to filgrastim Current serious systemic illness Uncontrolled bacterial, viral, or fungal infection Receiving experimental therapy or investigational agents History of cancer other than treated basal cell cancer of the skin or carcinoma in situ of the cervix. Cancer treated with curative intent \>5 yrs before donation will be reviewed on a case-by-case basis by the principal investigator