Comparing ATG or Post-Transplant Cyclophosphamide to Calcineurin Inhibitor-Methotrexate as GVHD Prophylaxis After Myeloablative Unrelated Donor Peripheral Blood Stem Cell Transplantation

PRIMARY OBJECTIVES:

I. To compare rates of chronic graft versus host disease (GVHD) between anti-thymocyte
globulin (ATG) or post-transplantation cyclophosphamide (PTCy) to calcineurin inhibitor
(CNI)-methotrexate.

SECONDARY OBJECTIVES:

I. To compare chronic GVHD, survival, GVHD-free relapse-free survival (GRFS), chronic
GVHD-free relapse-free survival (CRFS), grade II-IV and III-IV acute GHVD, relapse, and
non-relapse mortality between ATG and PTCy.

OUTLINE:

CONDITIONING REGIMENS:Participants receive 1 of 3 regimens and are randomized to 1 of 3 arms
for GVHD prophylaxis.

REGIMEN A: Participants undergo total body irradiation (TBI) on days -6 to -4 (-7 to -4 for
those < 18 years), then receive cyclophosphamide IV over 1-2 hours on days -3 and -2.
Participants randomized to Arm 2 only receive TBI on days -3 to -1 (-4 to -1 for those < 18
years).

REGIMEN B: Participants receive fludarabine phosphate IV and busulfan IV every 6 hours on
days -5 to -2.

REGIMEN C: Participants receive busulfan orally (PO) or IV every 6 hours on days -7 to -4 and
cyclophosphamide IV over 1-2 hours on days -3 and -2.

Myelofibrosis or other myeloproliferative neoplasms: Participants >= 18 years receive
cyclophosphamide IV over 1-2 hours on days -7 and -6 and busulfan IV on days -5 to -2.
Participants < 17 years receive busulfan IV every 6 hours on days -7 to -4 and
cyclophosphamide IV on days -3 and -2.

All participants undergo peripheral blood stem cell transplantation on day 0.

ARM 1: Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1.
Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV twice daily
(BID) tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease
progression or unacceptable toxicity.

ARM 2: Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day
5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the
absence of disease progression or unacceptable toxicity.

ARM 3: Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at
day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, participants are followed up at 6 months, then annually
thereafter.

Inclusion Criteria:

- The following diseases will be permitted, although other diagnoses can be considered
if approved by Fred Hutch Patient Care Conference or the participating institution's
patient review committees and the principal investigator:

- Acute lymphocytic leukemia (ALL) in complete remission (CR)1 with high risk
features defined as evidence of adverse cytogenetics such as t(9;22), t(1;19),
t(4;11), or MLL rearrangements or presence of minimal residual disease

- Acute myeloid leukemia (AML) in CR1 with high risk features defined as:

- Intermediate or adverse risk disease as defined by European LeukemiaNet
(ELN) 2017

- Greater than 1 cycle of induction therapy required to achieve remission

- Preceding myelodysplastic syndrome (MDS) or myelofibrosis

- Therapy-related AML

- Presence of FLT3 internal tandem duplications

- French-American-British (FAB) M6 or M7 classification

- Acute leukemia (ALL or AML) in second (2nd) or greater CR (CR > 2)

- Refractory or relapsed AML with =< 5% bone marrow blasts and no circulating
blasts by morphology or proven extramedullary disease

- Myelodysplastic syndrome (MDS) with following high risk features: poor
cytogenetics (-7, inv(3)/t(3q)/del(3q), del(7q) or complex cytogenetics defined
as >= 3 abnormalities), Revised International Prognostic Scoring System (IPSS-R)
risk group intermediate or higher, or treatment-related MDS

- Any phase of MDS if patient is < 21 years of age

- Chronic myelogenous leukemia (CML) beyond 1st chronic phase or resistant to
tyrosine kinase inhibitors (adults)

- Chronic myelomonocytic leukemia (CMML)

- Myeloproliferative disorders/myelofibrosis

- Hodgkin or non-Hodgkin lymphoma: relapsed chemotherapy-sensitive (complete or
partial response)

- Female patients must have negative beta-human chorionic gonadotropin (HCG) pregnancy
test (all women of child bearing-potential must have test performed)

- Ability to understand and the willingness to sign a written informed consent document

- For patients with acute leukemia, CR is defined as =< 5% marrow blasts by morphology.
CR with incomplete count recovery is allowed

- DONOR INCLUSION

- Unrelated donors matched for human leukocyte antigen (HLA)-A, B, C, DRB1 and DQB1 by
high resolution typing

- 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 hematopoietic cell transplantation (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

- Only granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem
cell (PBSC) will be permitted as a hematopoietic stem cell (HSC) source on this
protocol

- Donors must meet the selection criteria for administration of G-CSF and apheresis
defined based on each institution's standard practice protocol for unrelated donors

- Donors must be capable of giving informed consent

Exclusion Criteria:

- Prior autologous or allogeneic stem cell transplant

- Performance status: Karnofsky score <60 or Lansky score <50 for patients <16 years old

- Uncontrolled infection. The protocol principal investigator (PI) will be final arbiter
if there is uncertainty regarding whether a previous infection is under adequate
control to allow enrollment in the study

- Positive serology for human immunodeficiency virus (HIV)-1, 2 or human T-lymphotropic
virus (HTLV)-1, 2

- Left ventricular ejection fraction < 45%. Uncontrolled arrhythmias or symptomatic
cardiac disease

- Symptomatic pulmonary disease. Forced expiratory volume in 1 second (FEV1), forced
vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO) =< 50%
of predicted (corrected for hemoglobin). Use of continuous supplemental oxygen

- Calculated (Cockroft-Gault; or appropriate calculation for pediatric patients) serum
creatinine clearance <60 mL/min. If the calculated CrCl is 50-60 mL/min, but a
measured CrCl by 24 hour urine collection is > 60 mL/min, this measurement is
acceptable

- Total serum bilirubin more than twice upper normal limit

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3-fold
higher than laboratory upper normal limits

- History of allergy or anaphylactic reaction to rabbit protein or to any product
excipients

- Subjects may not be enrolled in other investigational trials with acute or chronic
GVHD as the primary endpoint

- DONOR EXCLUSION

- Donor who will exclusively donate marrow

- Donors who are HIV-positive

- Potential donors who for psychological, physiological, or medical reasons cannot
tolerate administration of G-CSF or apheresis

- Donors who are allergic to filgrastim or Escherichia (E.) coli-derived proteins

- Donor-related risks to recipients

- Positive anti-donor lymphocytotoxic crossmatch

- Pregnant or lactating women

- Prior malignancy within the last 5 years