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

Protocol # :
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
Chronic Myelomonocytic Leukemia
Disease Sites
Other Hematopoietic
Myeloid and Monocytic Leukemia
Principal Investigator
Koreth, John
Site Investigator
Koreth, John
Site Research Nurses
Beshere, Gianna
Brock, Jennifer
Halloran, Elizabeth
More, Avnee, P.

Trial Description

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).

Eligibility Requirements

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

- 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

- 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.