Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer

PRIMARY OBJECTIVES:

I. To evaluate the rate of relapse, defined as recurrence of underlying disease or
progression of underlying disease, at 1 year in patients who receive haploidentical
peripheral blood stem cells (PBSCs) after reduced intensity conditioning and post-transplant
cyclophosphamide.

SECONDARY OBJECTIVES:

I. To evaluate safety including development of acute graft versus host disease (GVHD) and
death at 100 days post-transplant, as well as other treatment related toxicities including
chronic GVHD, engraftment rate, non-relapse mortality, progression free survival (PFS) at one
year, and overall survival (OS) at one year, as compared with historical controls.

TERTIARY OBJECTIVES:

I. Correlative studies will include chimerism analysis by molecular analysis and evaluation
of immune reconstitution by cytomegalovirus (CMV) dextramer analysis using flow cytometry.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -6 to -2
and cyclophosphamide IV over 2 hours on days -6 and -5. Patients undergo total body
irradiation (TBI) on days -1 and peripheral blood stem cell transplantation (PBSCT) on day 0.

After completion of study treatment, patients are followed up at 30 and 100 days.

Inclusion Criteria:

- The patient must have a diagnosis of one of the following (one must be yes):

- Bone marrow failure disorders:

- Acquired bone marrow failure disorders include aplastic anemia, paroxysmal
nocturnal hemoglobinuria (PNH):

- SAA must have failed at least one cycle of standard immunosuppressive
therapy with calcineurin inhibitor plus anti-thymocyte globulin (ATG)
if a fully-matched donor is not available

- PNH must have failed treatment or not tolerated treatment with
eculizumab or progressed during or after treatment with eculizumab)

- Hereditary bone marrow failure disorders include Diamond-Blackfan anemia,
Shwachman-Diamond syndrome, Kostmann syndrome, and congenital
amegakaryocytic thrombocytopenia

- Other non-malignant hematologic or immunologic disorders that require
transplantation:

- Quantitative or qualitative congenital platelet disorders (including but not
limited to congenital amegakaryocytopenia, absent-radii syndrome,
Glanzmann's thrombasthenia)

- Quantitative or qualitative congenital neutrophil disorders (including but
not limited to chronic granulomatous disease, congenital neutropenia)

- Congenital primary immunodeficiencies (including but not limited to severe
combined immunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand
deficiency, T-cell deficiencies)

- Hemoglobinopathies (including sickle cell disease and thalassemia

- Acute leukemias:

- Acute myeloid leukemia (AML) - antecedent myelodysplastic syndrome,
secondary AML, high risk cytogenetic abnormalities or normal cytogenetics
with high-risk molecular mutations (including but not limiting to Flt3-ITD
mutation)

- Acute lymphoblastic leukemia (ALL) B cell or T cell

- Chronic myelocytic leukemia (CML):

- Chronic phase (intolerant or unresponsive to imatinib and/or tyrosine kinase
inhibitors)

- Second chronic phase or accelerated phase who are ineligible for
conventional myeloablative transplantation

- Myeloproliferative and myelodysplasia syndromes:

- Myelofibrosis (with/without splenectomy) with intermediate to high risk
features

- Advanced polycythemia vera not responding to therapy

- Myelodysplastic syndrome (MDS) with an International Prognostic Scoring
System (IPSS) score of intermediate or higher

- Secondary MDS with any IPSS score

- Chronic myelomonocytic leukemia (CMML)

- Lymphoproliferative disease:

- Chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL)
(recurrent or persistent) cytotoxic therapy refractory or with less than 6
months duration of complete response (CR) between courses of conventional
therapy

- Multiple myeloma (MM) progressive disease after auto bone marrow
transplantation (BMT), tandem allo after prior auto

- Waldenstrom?s macroglobulinemia (failed one standard regimen)

- T or B cell lymphoma with poor risk features

- Hodgkin disease:

- Received and failed frontline therapy

- Failed or not eligible for autologous transplantation

- Suitable related haploidentical donor identified:

- Must be matched at least at 5 of 10 HLA antigens (A, B, C,DRB1, DQ)

- Must not be matched at more than 7 of 10 HLA antigens

- Recipient should not have HLA antibodies to potential donor; if the recipient
does have HLA antibodies to the potential donor, an alternative donor is
preferred; however, if there are no suitable alternative donors, the donor to
whom the patient has HLA antibodies can be utilized as long as the antibody titer
is less than 2000 median fluorescence intensity (MFI); if the titer is > or = to
2000 MFI, the recipient must undergo successful antibody desensitization prior to
enrollment on this study; any patients who have demonstrated donor specific
antibodies will not be evaluated for the end points measured in this study but
will be followed for treatment related toxicities

- Haploidentical donors that are ABO compatible with the recipient are preferred.
Minor ABO incompatibility is preferred to major ABO incompatibility. Major ABO
incompatibility between recipient and donor is the least preferred but still
acceptable for this study.

- It is preferred that the haploidentical donor must be available to donate on day
-1 and day 0, so that fresh product can be processed by the Stem Cell lab and
administered to the patient on day 0.. While less preferable, cryopreserved
product may be utilized with this product.

- Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% predicted, corrected
for hemoglobin and/or alveolar ventilation

- Left ventricular ejection fraction > 40%

- Bilirubin, liver alkaline phosphatase, serum glutamic-oxaloacetic transaminase (SGOT)
or serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit of normal

- Calculated creatinine clearance > 40 cc/min by the modified Cockcroft-Gault formula
for adults or the Schwartz formula for pediatrics

- Have a Karnofsky (adult) or Lansky (for =< 16 years) performance status >= 60%

- Patient must be able to pass radiation evaluation (i.e.: able to receive 200 cGy)

- Patients who have failed a prior autologous transplant are eligible; however, at least
90 days must have elapsed between the start of this reduced intensity conditioning
regimen and the last transplant if patient had a prior autologous BMT

- Participants of child-bearing potential must agree to use adequate contraceptive
methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
entry; should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately

- Participant or legal representative must understand the investigational nature of this
study and sign an independent ethics committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

- Patient in CR or has a bone marrow failure disorder or non-malignant hematologic or
immune disorder : does NOT have a sibling donor or 12/12 HLA matched unrelated donor
available OR treating clinician considers haploidentical transplant referable (despite
sibling donor availability or 12/12 HLA matched donor availability) due to patient's
clinical status.

- Exclusion Criteria:

- Participants who have had chemotherapy, radiation treatment and/or surgery 2 weeks
prior to entering the study or, as per discretion of the treating physician, those who
have not recovered sufficiently from adverse events due to agents administered more
than 2 weeks earlier

- Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)

- Child-Pugh class B and C liver failure

- Concomitant active malignancy that would be expected to require chemotherapy within 3
years of transplant (other than non-melanoma skin cancer)

- Patients who have received maximally allowed doses (given in 2 Gy fractionations, or
equivalent) of previous radiation therapy to various organs; patients who previously
have received a higher than allowed dose of radiation to a small lung, liver and brain
volume, will be evaluated by the radiation oncologist to determine if the patient is
eligible for study

- Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or
other condition which, in the opinion of treating physician, would make this protocol
unreasonably hazardous for the patient

- Known human immunodeficiency virus (HIV) positive

- Pregnant or nursing female participants

- Patients who in the opinion of the treating physician are unlikely to comply with the
restrictions of allogeneic stem cell transplantation based on formal psychosocial
screening

- Patients with donor specific HLA antibodies with a titer greater than 2000 MFI
(whether or not they have undergone a desensitization protocol)

- Patients who have undergone a prior allogeneic hematopoietic or (other organ)
transplant

- Treating physician considers the potential HLA haploidentical donor to be ineligible
to receive G-CSF, and/or concern on the part of the treating physician for risk of
harm to the potential donor with administration of G-CSF, and/or refusal by the
potential donor (or donor?s guardian) to receive G-CSF

- Any condition which in the investigator?s opinion deems the participant an unsuitable
candidate to receive study drug

- Received an investigational agent within 30 days prior to enrollment