A phase 1 trial of CD25/Treg-depleted DLI plus Ipilimumab for myeloid disease relapse after matched-HCT

In this research study, our main goal for the ipilimumab portion of the study is to
determine the highest dose of ipilimumab that can be given safely in several courses and
to determine what side effects are seen in patients with Acute Myeloid Leukemia (AML),
Myelodysplastic Syndromes (MDS), Myeloproliferative Neoplasms (MPN), Chronic
Myelomonocytic Leukemia (CMML), or Myelofibrosis (MF).

Inclusion Criteria:

- Histologically or cytologically confirmed relapse of AML, MDS or MPN (CMML or
myelofibrosis or MDS/MPN with ≥5% blasts in the marrow).

- Relapse at ≥2 months after any 8/8 or better HLA-matched HCT

- Available original stem cell donor.

- Age ≥18 years. Because no dosing or adverse event data are currently available on
the use of Ipilimumab in participants <18 years of age, children are excluded from
this study.

- ECOG performance status ≤2 (Karnofsky performance status ≥60, see Appendix A).

- Recipient donor T cell chimerism ≥20% within 4 weeks prior to cell infusion.

- <50% bone marrow involvement within 4 weeks prior to cell infusion.

- No systemic corticosteroid therapy for GVHD (≤5 mg of prednisone or equivalent doses
of other systemic steroids for non-GVHD, non-autoimmune indications for at least 4
weeks prior to cell infusion).

- No other systemic medications/treatments (e.g. ECP) for GVHD for at least 4 weeks
prior to cell infusion.

- Ability to understand and willingness to sign written informed consents.

- Adequate organ function as defined below:

- Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except
Gilbert's or disease-related hemolysis, then < 3 x ULN)

- AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN

- creatinine clearance: ≤1.5 x institutional ULN

- O2 saturation: ≥90% on room air

- LVEF >40%

- The effects of CD25/Treg-depleted DLI and Ipilimumab on the developing human fetus
are unknown. For this reason and because immunomodulatory agents are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while participating in this study or within 23
weeks after the last dose of study drug, she should inform her treating physician
immediately. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation,
and for at least 31 weeks after completion of Ipilimumab administration.

- Negative pregnancy test for females of childbearing potential only

Exclusion Criteria:

- Extramedullary relapse involving immuno-privileged sites (e.g. CNS, testes, eyes).
Other sites of extramedullary relapse (e.g. leukemia cutis, granulocytic sarcoma)
are acceptable.

- Participants who have had anti-tumor chemotherapy or other investigational agents
within 4 weeks prior to cell infusion (6 weeks for nitrosoureas or mitomycin C), or
immunotherapy within 8 weeks prior, or those who have not recovered from adverse
events due to agents administered more than 4 weeks prior. Use of hydroxyurea to
control counts within 4 weeks prior to cell infusion is permitted.

- Prior history of DLI

- Prior history of treatment with anti-CTLA-4 or anti-PD-1 pathway therapy, or CD137
agonist therapy.

- Prior history of severe (grade 3 or 4) acute GVHD, or ongoing active GVHD requiring
systemic treatment.

- Organ transplant (allograft) recipient.

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to Ipilimumab or other agents used in study.

- Autoimmune disease: Patients with a history of inflammatory bowel disease, including
ulcerative colitis and Crohn's Disease, are excluded from this study, as are
patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic
progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
vasculitis [e.g., Wegener's Granulomatosis]) and motor neuropathy considered of
autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Patients
with Hashimoto's thyroiditis are eligible to go on study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance
with study requirements.

- Pregnant women are excluded from this study because of the unknown teratogenic risk.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother, breastfeeding should be discontinued if the
mother is treated on this study.

- HIV-positive participants on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with agents used in this
study. In addition, these participants are at increased risk of lethal infections
when treated with marrow- suppressive therapy. Appropriate studies will be
undertaken in participants receiving combination antiretroviral therapy when
indicated.

- Individuals with active uncontrolled hepatitis B or C are ineligible as they are at
high risk of lethal treatment-related hepatotoxicity after HCT.