A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) Followed by Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies

Inclusion Criteria:

1. Documentation of Disease: Patients must be diagnosed with one of the following conditions:

   1. Acute Myeloid Leukemia (AML), with no history of extramedullary disease, who are not in complete remission, who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:

      * Duration of first CR \< 6 months (if previously in CR), based on the best overall clinical assessment of the disease course, not solely based on blood test or bone marrow biopsy results
      * Poor risk karyotype including any of the following: complex karyotype with ≥3 clonal abnormalities, 5q-/-5, 7q-/-7, 11q23 abnormalities, inv(3q), 20q or 21q abnormalities, t (6;9), t (9;22), 17p abnormalities \[or TP53 mutations\] or monosomal karyotype. Molecular typing (except for TP53 mutation) will not be used for eligibility criteria determination.
      * Circulating peripheral blood blasts at time of enrollment
      * Karnofsky performance status \<90%
   2. Acute Lymphocytic Leukemia (ALL) who are not in complete remission, who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:

      * Primary refractory or first relapse. Patients in second or subsequent relapse are excluded.
      * Bone marrow blasts \>25% within 30 days before the start of the conditioning regimen
      * Age \>40 years
   3. Myelodysplasia with a Revised International Prognostic Score (IPSS-R) of greater than 4.5 (i.e., high- or very-high risk).
   4. Chronic Myelogenous Leukemia (CML) in accelerated phase, defined by any of the following:

      * 10-19% blasts in peripheral blood white cells or bone marrow
      * Peripheral blood basophils at least 20%
      * Persistent thrombocytopenia (\< 100 x 109/l) unrelated to therapy, or persistent thrombocytosis (\>1000 x 109/l) unresponsive to therapy
      * Increasing spleen size and increasing white blood cell (WBC) count unresponsive to therapy
      * Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase)
2. The patient must be 18-65 years old at time of consent
3. Signed written informed consent: Patient must be capable of understanding the investigational nature of this study, potential risks and benefits of the study, and be able to provide a valid informed consent.
4. Availability of a consenting human leukocyte antigens (HLA)-matched donor
5. Karnofsky Performance Status 70% or higher
6. Required baseline laboratory values:

   * Estimated creatinine clearance ≥ 60 ml/min
   * Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal value
   * Bilirubin ≤ 1.5 x upper limit of normal value (unless determined to be related to Gilbert's disease)
7. Required baseline cardiac function values:

   * Required baseline cardiac function of left ventricular ejection fraction (LVEF) \> 45 % corrected
8. Required baseline pulmonary function values:

   * Required baseline pulmonary function of lung diffusing capacity (DLCO) \> 45 % predicted (corrected for hemoglobin))

Exclusion Criteria:

1. HIV seropositive patients
2. Pregnant or nursing females.
3. Prior radiation therapy
4. Patients who have had a prior autologous or allogeneic bone marrow or stem cell transplantation
5. Gemtuzumab ozogamicin (trade name: Mylotarg) and/or inotuzumab ozogamicin (trade name: Besponsa) use within 60 days before start of the conditioning regimen
6. Though this is NOT an exclusion criterion, we strongly recommend discontinuation of any steroidal oral contraceptives at least 7 days before start of the conditioning regimen. Use of therapeutic alternatives, including leuprolide should be considered to reduce the risk of SOS/VOD. Of note, for patients already on steroidal oral contraceptives for excessive menorrhagia, the switch to leuprolide should occur at least 2 weeks before the start of the conditioning regimen