Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Patients With Secondary Myelofibrosis

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of reduced-intensity (FM) haploidentical
hematopoietic cell transplantation (Haplo-HCT) followed by post-transplant cyclophosphamide
(PTCy) in patients with advanced myelofibrosis (MF), as assessed by the evaluation of
toxicities, including type, frequency, severity, attribution, time course and duration.

SECONDARY OBJECTIVES:

I. To summarize and evaluate hematologic (neutrophil and platelet) recovery. II. To estimate
graft failure-free survival (GFS) at 100-days post-transplant. III. To estimate overall
survival (OS), progression-free survival (PFS) and cumulative incidence (CI) of
relapse/progression, and non-relapse mortality (NRM) at 100-days, 1-year, and 2-year post
transplant.

IV. To estimate the cumulative incidence of acute graft-versus-host disease (GvHD), grade
II-IV, at 100-days post-transplant (per Keystone Consensus modification of the Glucksberg
criteria).

V. To estimate the cumulative incidence of chronic GvHD at 1-year and 2-year post transplant
(per National Institutes of Health [NIH] Consensus Criteria).

VI. To characterize the severity and extent of acute and chronic GvHD.

TERTIARY OBJECTIVES:

I. To conduct correlative studies and describe inflammatory cytokine levels and GVHD
biomarker levels in plasma and T cell differentiation/functions in patients enrolled onto the
trial.

OUTLINE:

Patients receive melphalan intravenously (IV) over 30 minutes on day -5, fludarabine IV over
30-60 minutes on days -5 to -2. Patients undergo total body irradiation (TBI) on day -1 and
hematopoietic cell transplantation (HCT) on day 0. Patients receive cyclophosphamide IV over
1-2 hours on days 3 and 4. Starting on day 5, patients receive tacrolimus IV then orally (PO)
for 6 months followed by a taper, mycophenolate mofetil PO thrice daily (TID) until day 35,
and glycosylated recombinant human G-CSF AVI-014 (G-CSF) IV daily until absolute neutrophil
count > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease
progression or unexpected toxicity.

After completion of study treatment, patients are followed for up to 2 years.

Inclusion Criteria:

- Diagnosis of primary of secondary myelofibrosis with transplant indication by Dynamic
International Prognostic Scoring System (DIPSS)-plus (> intermediate-1)

- Patients >= age 50 must have a comorbidity score (hematopoietic cell
transplant-comorbidity index [HCT-CI]) < 4 (Sorror)

- Patients can be in chronic phase (CP) with bone marrow (BM) blast count =< 15% as long
as no evidence of disease acceleration per principal investigator (PI) and treating
physician's opinion or after progression to acute myeloid leukemia (AML) and achieved
=< 5% BM blasts (morphologic complete remission [CR] prior to transplant)

- Lack of an human leukocyte antigen (HLA) matched donor or need to proceed fast to
transplantation when a patient does not have an immediately available matched
unrelated donor (typed by high-resolution in the registry)

- Performance status >= 70% (Karnofsky); patients > 50 years should have adequate
cognitive function; any concerns regarding cognitive function should be addressed by a
geriatrician/neurologist

- Alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/bilirubin =< 5 X upper
limit of normal (ULN)

- Measured creatinine clearance > 60 mls/min

- Left ventricular ejection fraction (LVEF) >= 50%

- Corrected carbon monoxide diffusing capability (DLCOc) >= 50%

- No active infections

- Prior treatment with JAK2 inhibitor therapy is not excluded; a JAK2 inhibitor will
need to be stopped 1-2 days prior to starting conditioning regimen

- DONOR: Documented informed consent per local, state and federal guidelines

- DONOR: Genotypically haploidentical as determined by HLA typing

- Preferably a non-maternal HLA haploidentical relative due to data of high
incidence of graft failure with use of maternal HLA haploidentical cells

- Eligible donors include biological parents, siblings or half-siblings, children,
or cousins in rare instances

- DONOR: Absence of pre-existing donor-specific anti-HLA antibodies (DSA) in the
recipient; Patients with pre-existing DSA could undergo desensitization per City of
Hope (COH) standard operating procedures [SOP] and should have DS < 2000 prior to
conditioning at discretion of principal investigator (PI)

- DONOR: Infectious disease screening performed within 30 days prior to stem cell
mobilization per federal guidelines and is:

- Seronegative for HIV 1+2 antibody (Ab) and/or HIV polymerase chain reaction
(PCR), human T-cell leukemia virus (HTLV) I/II Ab, hepatitis B virus surface
antigen (HBsAg), hepatitis B virus surface antibody (HBcAb), hepatitis C virus
(HCV) Ab

- Negative rapid plasma reagin (RPR) for syphilis

- DONOR: Women of childbearing potential (WOCBP): Urine pregnancy testing performed
within 7 days prior to stem cell mobilization

- DONOR: Is approved and completed evaluation prior to recipient initiation of the
preparative regimen per institutional guidelines

Exclusion Criteria:

- Evidence of severe portal hypertension with evidence of decompensation either with
bleeding varices, large volume ascites, or hepatic encephalopathy

- In a bone marrow biopsy 4 weeks prior to start of conditioning on study:

- > 15% bone marrow blasts at transplant if no history of AML and per PI and
treating physician's opinion of disease acceleration

- > 5% if had previous progression to AML

- Human immunodeficiency virus (HIV) positive; active hepatitis B or C

- Patients with active infections; the principal investigator (PI) is the final arbiter
of the eligibility

- Liver cirrhosis

- Prior central nervous system (CNS) involvement by tumor cells

- Severe pulmonary hypertension (PHT) (on echo or right side cardiac catheterization)

- 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
papanicolaou [PAP] smear)

- Positive beta HCG test in a woman with child bearing potential defined as not
post-menopausal for 12 months or no previous surgical sterilization

- Noncompliance - inability or unwillingness to comply with medical recommendations
regarding therapy or follow-up, including smoking tobacco

- DONOR: Has undergone solid organ, stem cell, bone marrow or blood transplantation

- DONOR: Receiving any investigational agents, or concurrent biological, chemotherapy,
immunosuppression or radiation therapy

- DONOR: Active infection

- DONOR: Thrombocytopenia < 150,000 cells /mm^3 at baseline evaluation

- DONOR: Sero-positive for HIV-1 & 2 antibody, HTLV-I & II antibody, hepatitis B virus
(HBV) and HCV

- DONOR: Medical or physical reason which makes the donor unlikely to tolerate or
cooperate with growth factor therapy and leukapheresis

- DONOR: Factors which place the donor at increased risk for complications from
leukapheresis or G-CSF therapy

- DONOR: WOCBP: Pregnant or =< 6 months breastfeeding