A Randomized Phase II Study of Hyperbaric Oxygen in Improving Engraftment in Umbilical Cord Blood Stem Cell Transplant

However, UCB as a graft source for a bone marrow transplant has drawbacks related to the
limited cell dose available for transplant and defects in homing. Homing is the process of
UCB stem cell lodging in the bone marrow. If the homing is not efficient it could delay the
re-population of the stem cells (or engraftment), possibly lead to engraftment failure, and
delay the rebuilding of the immune system after transplant. This could, in turn, provide a
higher risk to infection after the UCB transplant.

This research study is aimed at investigating the use of hyperbaric oxygen (HBO) therapy
prior to the UCB transplant to find out if it will improve the stem cell homing, and
subsequently, the engraftment. HBO therapy involves breathing 100% pure oxygen while in a
sealed chamber that has been pressurized at 2 ½ times the normal atmospheric pressure.

There is a specific hormone which tells stem cells in the bone marrow to make more red blood
cells. This hormone (called EPO) is increased when blood oxygen levels are low. When the EPO
is increased, it might impair the bone marrow homing process of your transplant. Therefore,
the researchers conducting this study hope to determine if providing 100% pure oxygen to you
prior to your UCB transplant will decrease this hormone, and in turn, improve the homing
process after your transplant.

Inclusion Criteria:

- Voluntary written informed consent

- Patients who are considered for allogeneic transplantation based on their disease risk
(see below) but lack matched sibling or unrelated donors or who are unable to proceed
to allogeneic transplant within 8 weeks, will be considered for UCB transplantation on
this study. Only patients for whom RIC will be considered are eligible. RIC is
considered in those older than 45 or younger than 45 with Hematopoietic Cell
Transplant (HCT) Comorbidity Index of 3 or higher (HCT) Comorbidity Index can be
calculated using the following link: http://www.hctci.org/Home/Calculator

- Patients with acute myeloid leukemia (AML) in CR1 that is not considered
favorable-risk (favorable risk is defined as patients with t(15;17)(q22;q21),
t(8;21)(q22;q22), inv(16)(p13q22)/t(16;16)(p13;q22), NPM1 mutation without FLT3-ITD,
and double-mutated CEBPA58,59), AML in CR2 or subsequent CR, high-risk acute
lymphoblastic leukemia (ALL) in CR1, or ALL in CR2 or higher, biphenotypic leukemia
defined as coexpression of B-lymphoid and myeloid markers or T-lymphoid and myeloid
markers in the blast population60or undifferentiated leukemia in ≥CR1. Myelodysplatic
syndrome (MDS)/myeloproliferative neoplasm (MPN) patients with less than 10% bone
marrow blasts and no peripheral blood blasts on pre-transplant bone marrow
aspirate/biopsy are considered for FluCyTTBI regimen. Chemotherapy sensitive
(achievement of at least a partial response according to Lugano classification61)
Hodgkin's disease (HD) that relapsed following high-dose therapy. Chemotherapy
sensitive (achievement of at least a partial response according to Lugano
classification) non-Hodgkin's lymphoma (NHL) patients who relapsed post-high-dose
therapy and autologous transplantation. Subjects should be enrolled within 30 days of
transplant.

- For ALL, high-risk features are defined using modified Hoelzer risk criteria62, these
criteria are:

1. High white blood cell count at diagnosis (ie, >30,000/microL in B-ALL or
>100,000/microL in T-ALL).

2. Clonal cytogenetic abnormalities - t(4;11), t(1;19), t(9;22), or BCR-ABL gene
positivity.

3. Progenitor-B cell immunophenotype (eg, blasts expressing membrane CD19, CD79a,
and cytoplasmic CD22).

4. Length of time from start of induction therapy to attainment of CR greater than
four weeks.

5. Older age - >60 years old is high risk, 30 to 59 years old is intermediate risk.

6. MRD - a post-remission bone marrow MRD level ≥10-3 by molecular tests.

- Subjects must be ≥ 18 years old and ≤ 70 years old

- Karnofsky performance status (KPS) of ≥ 70% (Appendix A).

- Adequate hepatic, renal, cardiac and pulmonary function to be eligible for transplant.
Minimum criteria include:

- ALT, AST: < 4x IULN

- Total bilirubin: ≤ 2.0 mg/dL

- Creatinine: ≤ 1.5 x ULN

- EF measured by 2D-ECHO or MUGA scan of ≥ 45%

- FEV1, FVC and DLCO ≥ 50% of predicted value (corrected to serum hemoglobin).

- EKG with no clinically significant arrhythmia.

- Patients should have New York Heart Association (NYHA) Functional Classification,
class -1 (ordinary physical activity does not cause undue fatigue, palpitation,
dyspnea, or angina pain) or class II (ordinary physical activity results in fatigue,
palpitation, dyspnea, or angina pain).

- Patients should be evaluated for fitness for HBO by a hyperbaric oxygen trained
medical professional who is not part of the study team prior to starting preparative
regimen.

- Women of child-bearing potential should have a negative urine pregnancy test within 4
weeks of starting preparative regimen.

- Women of child-bearing potential and men with partners of child-bearing potential must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and for 30
days following completion of therapy. Should a woman or partner become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician and the investigator immediately.

- A woman of child-bearing potential is any female (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
following criteria:

1. Has not undergone a hysterectomy or bilateral oophorectomy; or

2. Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months)

Exclusion Criteria:

- Pregnant or breastfeeding

- Severe chronic obstructive pulmonary disease requiring oxygen supplementation

- History of spontaneous pneumothorax

- Active ear/sinus infection. Patients with chronic sinusitis or sinus headaches are
excluded unless cleared by ear, nose, throat provider.

- Evidence of pneumothorax or significant pulmonary fibrosis on chest imaging within 60
days of transplant.

- Prior chest surgery requiring thoracotomy or direct chest irradiation.

- Recent of sinus or ear surgery, excluding myringotomy or ear tubes (within the last 5
years).

- Claustrophobia

- Patients who had intrathecal chemotherapy within 2 weeks of starting preparative
regimen or cranial irradiation within 4 weeks of starting preparative regimen.

- History of seizures

- No active tobacco use 72 hours prior to transplant until complete transplant recovery.