Low-dose TBI Dose Escalation to Decrease Risks of Progression and Graft Rejection After Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning as Treatment for Untreated Myelodysplastic Syndrome or Myeloproliferative Disorders - A Multi-Center Trial

Inclusion Criteria:

- Patients aged >= 50 and < 75 years (yrs) with CMML, or previously untreated MDS or
MPD

- Patients aged < 50 yrs at high risk for regimen related toxicity using standard high
dose regimens; factors considered high risk include pre-existing conditions such as a
chronic disease affecting kidneys, liver, lungs, or heart or previous failed HCT

- An human leukocyte antigen (HLA)-identical related or an HLA-matched unrelated donor
(Fred Hutchinson Cancer Research Center [FHCRC] matching allowed will be Grade 1.0 to
2.1) is available

- Recovery from the effects of previous chemotherapy, with a minimum of 21 days from
initiation of last therapy; hydroxyurea or anagrelide may be used to manage elevated
cell counts in patients up to the time they begin therapy under this protocol

- Patients < 12 yrs of age must be discussed on a case by case basis with the primary
investigator (PI) of the protocol prior to registration

- A signed informed consent form or minor assent form

- MDS: MDS classifiable by the World Health Organization (WHO) system as RA, RARS,
refractory cytopenia with multilineage dysplasia (RCMD), RCMD and ringed sideroblasts
(RCMD-RS) or RAEB

- MDS: No previous myelosuppressive therapy; for the purpose of this protocol
myelosuppressive chemotherapy will be defined as chemotherapy given with the intent
of inducing a complete remission (e.g., standard 7+3, high dose intermittent ARA-C
[HIDAC], or Mylotarg)

- MDS: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be
documented by marrow examination within 3 weeks of initiation of conditioning

- CMML: Patients with CMML1 who have not received myelosuppressive therapy must have <
10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow
examination within 3 weeks of initiation of conditioning; OR patients with CMML who
have progressed beyond CMML1 and have received myelosuppressive chemotherapy must
have < 5% marrow blasts; fewer than 5% marrow blasts must be documented by marrow
examination within 3 weeks of initiation of conditioning

- MPD: Patients with polycythemia vera with persistent thrombotic or hemorrhagic
complications despite conventional therapy, or who have progressed to
postpolycythemic marrow fibrosis

- MPD: Patients with essential thrombocythemia with persistent thrombotic or
hemorrhagic complications despite conventional therapy, or who have progressed to
myelofibrosis

- MPD: Chronic idiopathic myelofibrosis with peripheral blood cytopenias

- MPD: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be
documented by marrow examination within 3 weeks of initiation of conditioning

- MPD: No previous myelosuppressive therapy; for the purpose of this protocol
myelosuppressive chemotherapy will be defined as chemotherapy given with the intent
of inducing a complete remission (e.g., standard 7+3, HIDAC, or Mylotarg)

- Atypical CML: Philadelphia chromosome-negative patients with a diagnosis of atypical
CML

- Atypical CML: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts
must be documented by marrow examination within 3 weeks of initiation of conditioning

- Atypical CML: No previous myelosuppressive therapy; for the purpose of this protocol
myelosuppressive chemotherapy will be defined as chemotherapy given with the intent
of inducing a complete remission (e.g., standard 7+3, HIDAC, or Mylotarg)

- Paroxysmal nocturnal hemoglobinuria (PNH): Patients with the non-aplastic form of PNH
(cellular bone marrow) who have had a history of life-threatening complications of
their disease including thrombotic events, severe hemolysis or Budd Chiari syndrome
are eligible; other patients may be considered following approval at PCC and approval
by the Principal investigator

- Matched Related Donor: Related to the patient and is genotypically or phenotypically
HLA-identical

- Matched Related Donor: Donor age < 75 yrs unless cleared by institutional PI

- Matched Related Donor: Capable of giving written, informed consent

- Matched Related Donor: Donor must consent to PBSC mobilization with G-CSF and
apheresis

- Unrelated Donor: FHCRC matching allowed will be Grades 1.0 to 2.1: Unrelated donors
who are prospectively:

1. Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing;

2. Only a single allele disparity will be allowed for HLA-A, B, or C as defined by
high resolution typing

- Unrelated Donor: Patient and donor pairs homozygous at a mismatched allele in the
graft rejection vector are considered a two-allele mismatch, i.e., the patient is
A*0101 and the donor is A*0102, and this type of mismatch is not allowed

- HLA Matched Related Donor: G-CSF mobilized peripheral blood mononuclear cell (PBMC)
only will be permitted as a hematopoietic stem cell (HSC) source on this protocol

- HLA Matched Unrelated Donor: Donor must consent to PBSC mobilization with G-CSF and
apheresis; bone marrow unrelated donors are not eligible for this protocol

Exclusion Criteria:

- Organ dysfunction as defined by the following:

- Symptomatic coronary artery disease or cardiac ejection fraction < 35% (or, if
unable to obtain ejection fraction, shortening fraction of <26%); if shortening
fraction is <26% a cardiology consult is required with the PI having final
approval of eligibility; ejection fraction is required if age > 50 years or
there is a history of anthracycline exposure or history of cardiac disease

- Diffusing capacity of the lung for carbon monoxide (DLCO) < 35%, TLC < 35%,
forced expiratory volume (FEV)1 < 35% and/or receiving supplementary continuous
oxygen; the FHCRC PI of the study must approve of enrollment of all patients
with pulmonary nodules

- Liver function abnormalities: Patient with clinical or laboratory evidence of
liver disease will be evaluated for the cause of liver disease, its clinical
severity in terms of liver function, bridging fibrosis, and the degree of portal
hypertension; the patient will be excluded if he/she is found to have fulminant
liver failure, cirrhosis of the liver with evidence of portal hypertension,
alcoholic hepatitis, esophageal varices, a history of bleeding esophageal
varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction
evinced by prolongation of the prothrombin time, ascites related to portal
hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic
viral hepatitis with total serum bilirubin > 3mg/dL, or symptomatic biliary
disease

- Bone marrow documenting blast count >= 10% or >= 5% in CMML patients who have
progressed beyond CMML1 and received myelosuppressive chemotherapy

- Patients with active non-hematologic malignancies (except non-melanoma skin cancers);
this exclusion does not apply to patients with non-hematologic malignancies that do
not require therapy

- Patients with a history of non-hematologic malignancies (except non-melanoma skin
cancers) currently in a complete remission, who are less than 5 years from the time
of complete remission, and have a > 20% risk of disease recurrence

- Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by
standard pathology

- Active central nervous system (CNS) involvement of disease

- Karnofsky performance score < 70% or Lansky-Play Performance score < 70 for pediatric
patients

- Life expectancy severely limited by diseases other than malignancy

- Fungal infections with radiological progression after receipt of amphotericin product
or active triazole for > 1 month

- Active bacterial infection

- Patients of fertile age who refuse contraception for a twelve month period
post-transplant

- Females who are pregnant or breastfeeding

- Human immunodeficiency virus (HIV) seropositivity

- Severe psychological illness such as major psychosis (e.g. schizophrenia), major
bipolar depression, or suicidal situational depression

- Matched Related Donor: Identical twin

- Matched Related Donor: Any contra-indication to the administration of subcutaneous
G-CSF at a dose of 16mg/kg/d for five consecutive days

- Matched Related Donor: Serious medical or psychological illness

- Matched Related Donor: Pregnant or lactating females

- Matched Related Donor: Prior malignancy within the preceding five yrs, with the
exception of non-melanoma skin cancers

- Matched Related Donor: HIV seropositivity

- Unrelated Donor: A positive anti-donor cytotoxic crossmatch is an absolute donor
exclusion; donors are excluded when preexisting immunoreactivity is identified that
would jeopardize donor hematopoietic cell engraftment; this determination is based on
the standard practice of the individual institution; the recommended procedure for
patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
reactive antibody (PRA) screens to class I and class II antigens for all patients
before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell
cytotoxic cross matches should be obtained; the donor should be excluded if any of
the cytotoxic cross match assays are positive; for those patients with an HLA Class I
allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be
obtained regardless of the PRA results

- Unrelated Donor: Marrow donors

- Unrelated Donor: Donors who are HIV-positive and/or medical conditions that would
result in increased risk to the donor G-CSF mobilization and G-PBMC collections

- Unrelated Donor: Serious medical or psychological illness

- Unrelated Donor: Pregnant or lactating females

- Unrelated Donor: Prior malignancy within the preceding five yrs, with the exception
of non-melanoma skin cancers

- Unrelated Donor: HIV seropositivity