High Dose Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil in Preventing Graft Versus Host Disease in Patients With Hematological Malignancies Undergoing Myeloablative or Reduced Intensity Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To estimate the graft versus host disease (GVHD)-free relapse/progression-free survival
(GRFS) at one-year post hematopoietic cell transplantation (HCT) and to evaluate the clinical
activity of post-transplant high dose cyclophosphamide (PTCy).

SECONDARY OBJECTIVES:

I. To summarize toxicities/complications/infections including type, frequency, severity,
attribution, time course and duration through 100 days post-transplant.

II. To estimate the cumulative incidence (CI) of acute and chronic GVHD. III. To characterize
the time course of neutrophil and platelet recovery/engraftment.

IV. To estimate overall survival (OS), progression-free survival (PFS), CI of
relapse/progression and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

V. To describe quality of life at 100 days, 6 months, 1 and 2 years. VI. To characterize
immune cell reconstitution and T cell repertoire post high dose cyclophosphamide in
mismatched donor HCT.

VII. To characterize quality of life.

OUTLINE:

CONDITIONING REGIMEN: Patients are assigned to 1 of 3 conditioning regimens at the discretion
of the attending physician and principal investigator.

REGIMEN A (REDUCED INTENSITY CONDITIONING): Patients receive fludarabine phosphate
intravenously (IV) over 60 minutes on days -7 to -3 and melphalan hydrochloride IV over 20
minutes on day -2.

REGIMEN B (MYELOABLATIVE CONDITIONING [MAC]): Patients receive fludarabine phosphate IV over
1-3 hours and busulfan IV over 3 hour on days -5 to -2.

REGIMEN C (MAC): Patients receive fludarabine phosphate IV over 60 minutes on days -7 to -5
and total body irradiation (TBI) twice daily (BID) on days -4 to -1.

TRANSPLANT: Patients undergo peripheral blood stem cell (PBSC) hematopoietic cell
transplantation (HCT) on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4,
mycophenolate mofetil IV or orally (PO) thrice daily (TID) beginning on day 5 and stopping on
day 35 if no severe GVHD is present, and tacrolimus IV continuously on days 5-180 with a
taper beginning on day 90 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up twice weekly for 100 days,
twice monthly for 6 months, monthly until no evidence of GVHD, and then yearly for up to 2
years.

Inclusion Criteria:

- Patients with acute leukemia or chronic myelogenous leukemia with no circulating
blasts and with less than 10% blasts in the bone marrow

- Patients with myelodysplastic syndrome (MDS) with intermediate-2 or high risk per
International Prognostic Scoring System (IPSS) (or intermediate, high, very high risk
by Revised International Prognostic Scoring System [IPSS-R]) or myeloproliferative
neoplasm; primary or secondary if high-risk features or refractory disease

- Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular,
marginal zone, diffuse large B-cell, Hodgkin lymphoma, or mantle cell lymphoma with
chemosensitive disease at time of transplantation; all types of lymphoma are eligible

- High risk, or refractory and relapsed multiple myeloma

- No available human leukocyte antigen (HLA)-matched related donor

- Available matched unrelated donor

- Ejection fraction at rest >= 50%

- Karnofsky performance status (KPS) >= 70

- Measured creatinine clearance more than 60 mL/min. The updated Schwartz formula should
be used for pediatric patients (>=5 to 12 years old)

- Carbon monoxide diffusing capability test (DLCO) >= 50% (adjusted for hemoglobin) and
forced expiratory volume in 1 second (FEV1) >= 50%

- Total bilirubin < 1.5 x the upper limit of normal; patients who have been diagnosed
with Gilbert's disease are allowed to exceed the defined bilirubin value of 1.5 x the
upper limit of normal

- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x the upper
limit of normal

- Alkaline phosphatase < 2.5 x the upper limit of normal

- Female subjects (unless postmenopausal for at least 1 year before the screening visit,
or surgically sterilized), agree to practice two (2) effective methods of
contraception at the same time, or agree to completely abstain from heterosexual
intercourse, from the time of signing of the informed consent through 12 months
post-transplant

- Male subjects (even if surgically sterilized), of partners of women of childbearing
potential must agree to one of the following: practice effective barrier
contraception, or abstain from heterosexual intercourse from the time of signing the
informed consent through 12 months post-transplant

- All subjects must have the ability to understand and the willingness to sign a written
informed consent document

DONOR INCLUSION CRITERIA

- 7 out of 8 at high resolution using deoxyribonucleic acid (DNA)-based typing with
either antigen or allele mismatched HLA (-A, -B, -C, and -DR) or 8/8 HLA-mismatched
with either double DQ mismatch (10/12) or combined DQ and DP mismatch

- Donor must be willing to donate peripheral blood stem cells

- Suitable donor

- Medically cleared to donate per National Marrow Donor Program (NMDP)

- Absence of donor-specific antibodies (DSA) to the mismatched HLA-locus

- Donor choices per matched unrelated donor (MUD) committee according to center standard
operating procedure (SOP)

Exclusion Criteria:

- Prior allogeneic transplant

- Active central nervous system (CNS) involvement by malignant cells

- Patients with uncontrolled bacterial, viral or fungal infections (currently taking
medication and with progression or no clinical improvement) at time of enrollment

- Patients with transformed lymphoma (e.g., Richter's transformation arising in
follicular lymphoma or chronic lymphocytic leukemia)

- Patients seropositive for the human immunodeficiency virus (HIV)

- Patients with active hepatitis B or C determined by polymerase chain reaction (PCR)

- Myocardial infarction within 6 months prior to enrollment or New York Heart
Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities; prior to study entry, any
electrocardiography (ECG) abnormality at screening must be documented by the
investigator as not medically relevant

- Female patients who are lactating or pregnant

- Patients with a serious medical or psychiatric illness likely to interfere with
participation in this clinical study

- History of another primary malignancy that has not been in remission for at least 3
years (the following are exempt from the 3-year limit: non-melanoma skin cancer, fully
excised melanoma in situ [Stage 0], curatively treated localized prostate cancer, and
cervical or breast carcinoma in situ on biopsy or a squamous intraepithelial lesion on
PAP smear)

- Psychosocial issues: no appropriate caregivers identified, or non-compliant to
medications

- Subjects, who in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study