Inclusion Criteria:
1. Voluntary signed and dated IRB/IEC approved written informed consent form in
accordance with regulatory and local guidelines.
2. Be 18 years or older and 70 years or younger on the day of signing consent
3. 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+ AML) or IPSS intermediate -2 or high risk myelodysplastic syndrome (MDS)
(Appendices A and B).
4. Have an available 6/6 related donor or an unrelated donor with a 10/10 match for
HLA-A, B, C, DRB1 and DQ antigen who consents to provide a marrow or peripheral blood
stem cell allograft. Typing is by DNA techniques: intermediate resolution for A, B and
C, and high resolution for DRB1/DQ
5. Be receiving one of the following conditioning regimen: fludarabine at a dose of 30
mg/m2 IV daily for 5 days, busulfan at a dose of 130 mg/m2 IV daily for 2 days, and
rabbit antithymocyte globulin (ATG) at a dose of 2 mg/kg IV daily for 2 days OR
fludarabine at a dose of 30 mg/m2 IV daily for 4 days, melphalan at a dose of 140
mg/m2 for one day with or without ATG at a dose of 2 mg/kg IV daily for 2 days
6. Be deemed eligible for an allogenic stem cell transplantation as per institutional
guidelines of the Blood and Marrow Transplantation Program at John Theurer Cancer
Center at Hackensack University Medical Center
7. Patients with adequate organ function as measured by:
- Cardiac: left ventricular ejection fraction at rest > 50%
- Hepatic: serum total bilirubin < 1.5x upper limit of normal for age as per local
laboratory (with the exception of isolated hyperbilirubinemia due to Gilbert's
syndrome); ALT and AST < 4x upper limit of normal for age as per local laboratory
- Renal: serum creatinine < 2x 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 1.73m2
body surface area) is required.
- Pulmonary: FEVl, FVC and DLCO (corrected for Hb) >50% predicted.
8. Have a performance status of 2 or lower on ECOG performance scale.
9. 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.
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10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of 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. See Note below for definition of WOCBP.
11. Women must not be breastfeeding.
12. 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). See Note
below for definition of WOCBP.
13. 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. See Note below for definition of WOCBP.
Exclusion Criteria:
1. 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 (eg, contrast dye allergy) or for treatment of non-autoimmune conditions
(eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
2. Is unable or unwilling to sign informed consent.
3. 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
4. Patients should be excluded if they have a condition such as GVHD 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 inhalation
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 (eg, contrast dye allergy) or for
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction
caused by contact allergen) is permitted.
5. As there is potential for hepatictoxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with a predisposition to hepatoxicity should be used with caution
in patients treated with nivolumab-containing regimen.
6. Has received a prior allogeneic stem cell transplant.
7. Has a history of hypersensitivity to nivolumab, ipilimumab, or any of its excipients,
or severe hypersensitivity reaction to any previous monoclonal antibody.
8. 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.
9. 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 (eg. 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 (eg, contrast dye allergy) or for treatment of non-autoimmune conditions
(eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has an active infection requiring intravenous systemic therapy.
12. 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.
13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
14. 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.
15. 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.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or
known acquired immunodeficiency syndrome (AIDS).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
18. Has the presence of a large accumulation of ascites or pleural effusions, which would
be a contraindication to the administration of methotrexate for GVHD prophylaxis.
19. Has known history of grade 3 or 4 GVHD.
