JAK Inhibitor Before Donor Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis

PRIMARY OBJECTIVES:

I. To optimize the role of allogeneic transplantation for primary and secondary myelofibrosis
(MF) in the JAK inhibitor era.

OUTLINE:

PART 1: Patients receive a ruxolitinib orally (PO) twice daily (BID) from at least 8 weeks
prior to the start of conditioning until best response through day -4 before transplantation,
with a taper schedule reducing the dose every 2-3 days beginning after day -4.

PART 2: Patients are assigned to 1 of 2 conditioning regimens at the discretion of the
clinical provider and Clinical Coordinators Office (CCO).

MYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 1
hour on days -8 to -6 (umbilical cord blood transplant recipients only), cyclophosphamide IV
on days -7 and -6, and busulfan IV over 3 hours on days -5 to -2.

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days
-6 to -2 and melphalan IV over 15-30 minutes on days -3 and -2. Patients also undergo
total-body irradiation (TBI) on day -1 (umbilical cord blood transplant recipients only).

TRANSPLANT: Patients undergo allogeneic hematopoietic stem cell transplant or umbilical cord
blood transplant on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus IV continuously
(inpatients) or over 1-2 hours twice daily (BID) (outpatients) or orally (PO) BID on days -1
to +180 (patients receiving related or unrelated stem cells) or days -3 to +180 (patients
receiving umbilical cord blood) with taper beginning on day +56 (related donor recipients) or
+100 (unrelated donor or umbilical cord blood recipients) in the absence of GVHD. Patients
also receive methotrexate IV on days +1, +3, +6, and +11 (related and unrelated donor
recipients only) or mycophenolate mofetil IV or PO every 8 hours on days 0 to +40 with taper
to day +96 (umbilical cord blood transplant recipients only).

After completion of study treatment, patients are followed up at 6 months, 1 year, and then
yearly for 4 years.

Inclusion Criteria:

PART 1:

- PART 1: Disease criteria

- Diagnosis of primary MF (PMF) as defined by the 2008 World Health Organization
classification system or diagnosis of secondary MF as defined by the
International Working Group (IWG) for Myeloproliferative Neoplasms Research and
Treatment criteria

- Patients meeting the criteria for intermediate-1, intermediate-2 or high-risk
disease by the Dynamic International Prognostic Scoring System (DIPSS) or
DIPSS-plus scoring system

- PART 1: Ability to understand and the willingness to sign a written informed consent
document

- PART 1: Patient must be a potential hematopoietic stem cell transplant candidate

PART 2:

- PART 2: Meeting criteria for 1st phase as above, at time of initiation of JAK
inhibitor, including ability to understand and willingness to sign a written informed
consent; patients arriving to our institution for transplant and not enrolled in Part
1 may still be enrolled in Part 2 if Part 1 criteria met; these patients will have
Part 1 endpoints transcribed from medical records

- PART 2: Received ruxolitinib for at least 8 weeks immediately prior to conditioning
and be able to continue until Day -4 pre-transplant

- PART 2: Performance status score

- Karnofsky >= 70

- PART 2: Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hr
urine creatinine clearance must be > 60 ml/min

- PART 2: Total serum bilirubin must be < 3 mg/dL unless the elevation is thought to be
due to Gilbert's disease or hemolysis

- PART 2: Transaminases must be < 3 x the upper limit of normal

- PART 2: Patients 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, and the degree of portal hypertension; patients with fulminant liver
failure, cirrhosis with evidence of portal hypertension or bridging fibrosis,
alcoholic hepatitis, hepatic encephalopathy, or correctable hepatic synthetic
dysfunction evidenced by prolongation of the prothrombin time, ascites related to
portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral
hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will
be excluded

- PART 2: Diffusing capacity of the lung for carbon monoxide (DLCO) corrected > 60%
normal

- May not be on supplemental oxygen

- PART 2: Left ventricular ejection fraction > 40% OR

- PART 2: Shortening fraction > 26%

- PART 2: Comorbidity Index < 5 at the time of pre-transplant evaluation

DONOR:

- DONOR: Human leukocyte antigen (HLA)-matched or 1 antigen mismatched sibling donor

- DONOR: 10 of 10 HLA-matched or 1 allele mismatched (9 of 10) unrelated donor

- DONOR: Peripheral blood is preferred over bone marrow for non-umbilical cord blood
recipients

- DONOR: Umbilical cord blood units will be selected according to the following
umbilical cord blood graft selection criteria; one or 2 cord blood (CB) units may be
used to achieve the required cell dose

- DONOR: The CB graft(s) must be matched at 4-6 HLA-A, B, DR Beta 1 (DRB1) loci with the
recipient and therefore may include 0-2 mismatches at the A or B or DRB1 loci; unit
selection will be based on cryopreserved nucleated cell dose and intermediate
resolution A, B antigen and DRB1 allele typing for determination of HLA-match; while
HLA-C antigen/allele level typing is not considered in the matching criteria, if
available, it may be used to optimize unit selection

- DONOR: Selection of two CB units is allowed to provide sufficient cell dose (see below
for algorithm to determine single versus double unit transplant); when multiple units
are selected, the following rules apply:

- The CB unit with the least HLA disparity (with the patient) will be selected
first (i.e., selection priority is 6/6 match > 5/6 match > 4/6 match); additional
CB units then may be selected to achieve the required cell dose, as outlined
below; if a second unit is required, this unit will be the unit that most closely
HLA matches the patient and meets minimum size criteria outlined below of at
least 1.5 x 10^7 total nucleated cells (TNC)/kg (i.e. a smaller, more closely
matched unit will be selected over a larger, less well matched unit as long as
minimum criteria are met)

- If two CB units are used:

- The total cell dose of the combined units must be at least 3.0 x 10^7 TNC
per kilogram recipient weight

- Each CB unit MUST contain at least 1.5 x 10^7 TNC per kilogram recipient
weight

- Algorithm for determining single versus double unit cord blood transplant:

- Match grade 6/6: TNC dose >= 2.5 x 10^7/kg

- Match grade 5/6, 4/6: TNC dose >= 4.0 (+/- 0.5) x 10^7/kg

- DONOR: General comments:

- Units will be selected first based on the TNC dose and HLA matching

- Cluster of differentiation (CD)34+ cell dose will not be used for unit selection
unless 2 units of equal HLA-match grade and similar TNC dose (+/- 0.5 x 10^7
TNC/kg) are available; in this case, the unit with the larger CD34+ cell dose (if
data available) should be selected

- A CB unit that is 5/6 mismatched but homozygous at the locus of mismatch should
be chosen over a 5/6 unit with bidirectional mismatch even if the latter unit is
larger (has more cells); this also applies to 4/6 units; this is only applicable
to choosing units within a given match grade

- Other factors to be considered:

- Within the same HLA match grade, matching at DR takes preference

- Cord blood banks located in the United States are preferred

- Up to 5% of the cord blood product(s), when ready for infusion, may be withheld
for research purposes as long as thresholds for infused TNC dose are met; these
products will be used to conduct studies involving the kinetics of engraftment
and immunobiology of double cord transplantation

Exclusion Criteria:

PART 1:

- PART 1: Evidence of human immunodeficiency virus (HIV) infection or known HIV positive
serology

- PART 1: Uncontrolled viral, bacterial, or fungal infections at the time of study
enrollment

- PART 1: History of prior allogeneic transplant

- PART 1: Pregnant or breastfeeding (only if patients have not been started on
ruxolitinib [Rux] by their primary oncologist prior to enrollment)

PART 2:

- PART 2: Uncontrolled viral or bacterial infection at the time of study enrollment

- PART 2: Active or recent (prior 6 month) invasive fungal infection without infectious
disease (ID) consult and approval

- PART 2: History of HIV infection

- PART 2: Pregnant or breastfeeding

- PART 2: Patients without an HLA-identical or 1-allele-mismatched related donor or
unrelated donor or umbilical cord blood units that meet transplant criteria