Nivolumab and/or Ipilimumab after Donor Blood Stem Cell Transplantation for the Treatment of Acute Myeloid Leukemia or Myelodysplastic Syndrome at High Risk for Post-Transplant Recurrence

Inclusion Criteria

• Voluntary signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and local guidelines
• Have a confirmed diagnosis of non-M3 acute myeloid leukemia (AML) (intermediate-II is high risk. Our population will consist of intermediate-II and high risk patients or any FLT3 positive [+] AML) or International Prognostic Scoring System (IPSS) intermediate -2 or high risk myelodysplastic syndrome (MDS)
• Have an available 6/6 related donor or an unrelated donor with a 10/10 match for human leukocyte antigen (HLA)-A, B, C, DRB1 and DQ antigen who consents to provide a marrow or peripheral blood stem cell allograft. Typing is by deoxyribonucleic acid (DNA) techniques: intermediate resolution for A, B and C, and high resolution for DRB1/DQ
• Be receiving one of the following conditioning regimen: fludarabine at a dose of 30 mg/m^2 IV daily for 5 days, busulfan at a dose of 130 mg/m^2 IV daily for 2 days, and rabbit antithymocyte globulin (ATG) at a dose of 2 mg/kg IV daily for 3 days OR fludarabine at a dose of 30 mg/m^2 IV daily for 4 days, melphalan at a dose of 140 mg/m^2 for one day with or without ATG at a total dose of 4 mg/kg IV over 3 days
• Be deemed eligible for an allogeneic stem cell transplantation as per institutional guidelines of the Blood and Marrow Transplantation Program at John Theurer Cancer Center at Hackensack University Medical Center
• Left ventricular ejection fraction at rest > 50%
• Serum total bilirubin < 1.5 x upper limit of normal for age as per local laboratory (with the exception of isolated hyperbilirubinemia due to Gilbert’s syndrome)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 4 x upper limit of normal for age as per local laboratory
• Serum creatinine < 2 x upper limit of normal for age (as per local laboratory). For patients with serum creatinine above the normal range, a glomerular filtration rate (measured as per institutional practice, typically creatinine clearance) equal to or greater than 60 mL/min (corrected to 1.73m^2 body surface area) is required
• Forced expiratory volume (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin [Hb]) > 50% predicted
• Have a performance status of 2 or lower on Eastern Cooperative Oncology Group (ECOG) performance scale
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of nivolumab. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should agree to ongoing pregnancy testing, to be performed prior to each dosing of ipilimumab and nivolumab
• Women must not be breastfeeding
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab, and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product, even if they have had a vasectomy. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception)
• Females of childbearing potential must be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 years * NOTE: Women of childbearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 * Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period of 23 weeks after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days

Exclusion Criteria

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 20 mg/day prednisone equivalents) for at least 4 weeks prior to study drug administration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Is unable or unwilling to sign informed consent
• Has an active, known, or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 20 mg daily prednisone equivalents) or other immunosuppressive medications within 4 weeks of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 20 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen
• Has received a prior allogeneic stem cell transplant
• Has a history of hypersensitivity to nivolumab, ipilimumab, or any of its excipients, or severe hypersensitivity reaction to any previous monoclonal antibody
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to day 1 of checkpoint inhibitor treatment administration or who has not recovered (i.e., t administration mAb) within 4 weeks prior to t dose of trial treatment. Rituximab within that time frame is allowed
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has an active infection requiring intravenous systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA], [qualitative] is detected)
• Has the presence of a large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for graft versus host disease (GVHD) prophylaxis
• Has known history of grade 3 or 4 GVHD